Submit
Browse All

The Journal of Visualized Experiments (JoVE) is a peer reviewed, PubMed-indexed video journal. Our mission is to increase the productivity of scientific research.

Recommend to Librarian

In JoVE (5)

Other Publications (125)

Articles by Kwok-Fai So in JoVE

 JoVE General

Micro-dissection of Rat Brain for RNA or Protein Extraction from Specific Brain Region


JoVE 269 8/30/2007

, , , ,

Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, The University of Hong Kong - HKU

Micro-dissection of rat brain into various regions is extremely important for the study of different neurodegenerative diseases. This video demonstrates micro-dissection of four major brain regions include olfactory bulb, frontal cortex, striatum and hippocampus in fresh rat brain tissue. Useful tips for quick removal of respective regions to avoid RNA and protein degradation of the tissue are given.

 JoVE General

Laser-Induced Chronic Ocular Hypertension Model on SD Rats


JoVE 549 12/04/2007

, ,

Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, The University of Hong Kong - HKU

Glaucoma is one of the major causes of blindness in the world. Elevated intraocular pressure is a major risk factor. Laser photocoagulation induced ocular hypertension is one of the well established animal models. This video demonstrates how to induce ocular hypertension by Argon laser photocoagulation in rat.

 JoVE General

Retrograde Labeling of Retinal Ganglion Cells by Application of Fluoro-Gold on the Surface of Superior Colliculus


JoVE 819 6/17/2008

, , , ,

The University of Hong Kong - HKU

This video describes the method of retrograde labeling of RGC by applying fluoro-gold (FG) on the surface of superior colliculus (SC). Technique involves drilling the skull, aspirating the cortex, and applying gelatin sponge over entire dorsal surface of SC.

 JoVE Neuroscience

Morphometric Analyses of Retinal Sections


JoVE 3377 2/19/2012

1, 1, 1, 1, 1,2,3, 1,2,3

1Laboratory of Neurodegenerative Diseases, Department of Anatomy, LKS Faculty of Medicine, The University of Hong Kong, 2Research Centre of Heart, Brain, Hormone and Healthy Aging, LKS Faculty of Medicine, The University of Hong Kong, 3State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong

This video demonstrates three types of morphometric analyses of the retina, which include measuring the inner nuclear layer thickness, quantifying the number of retinal ganglion cells (RGCs) and measuring the sizes of RGCs. The technique can offer a simple but scientific platform for morphometric analyses.

Other articles by Kwok-Fai So on PubMed

A Morphometric Study of Optic Axons Regenerated in a Sciatic Nerve Graft of Adult Rats

Restorative Neurology and Neuroscience. 2000  |  Pubmed ID: 12671213

PURPOSE: In the present study we have morphometrically examined a regeneration model in which axons normally residing in CNS have regrown and are interacting with Schwann cells from the PNS. This study will not only provide morphometric data on regenerated optic fibers but also shed light on possible factors in determining the fiber morphometry. METHODS: The optic nerves of rats aged 6 weeks were cut intra-orbitally and replaced with a autologous sciatic nerve. After a survival period of 9 months, the graft or "regenerated" nerves containing the regenerated optic axons and Schwann cells were processed for morphometric measurements. RESULTS: The mean myelinated axon diameter of regenerated nerve (1.8 +/- 0.2 micro m) was significantly (P < 0.05) greater than that of the optic nerve (0.9 +/- 0.03 micro m). However, unmyelinated regenerated optic axons had a smaller mean axon diameter (0.49 +/- 0.04 micro m) than normal myelinated optic axons. This may suggest that myelinating glial cells exert an influence on axon caliber and Schwann cells seem to have greater effect than oligodendrocytes. The mean g-ratio showing the relative myelin sheath thickness was found to be the highest in the optic nerve (0.78 +/- 0.003), least in the sciatic nerve (0.6 +/- 0.009) and intermediate in the regenerated nerve (0.68 +/- 0.01). The results indicated that Schwann cells myelinating the regenerated optic axons have produced a thinner myelin sheath. Intra-axonally, no significant difference was detected in the number of axonal microtubules and neurofilaments between the regenerated and optic nerves. Therefore the disposition of microtubules and neurofilaments into axon may be intrinsically determined. CONCLUSIONS: In this study, we have identified some of the extrinsic and intrinsic factors in determining the fiber morphometry of the regen-erated nerve. The axon-size and myelination by glial cells were determined through the external axon-glial interactions, whereas the number of axonal microtubules and neurofilaments were intrinsically determined.

Enhanced Survival and Regeneration of Axotomized Retinal Ganglion Cells by a Mixture of Herbal Extracts

Journal of Neurotrauma. Mar, 2002  |  Pubmed ID: 11939504

The aim of this study is to investigate the effects of Panax quinquefolius L. extract (PQE), Ginkgo biloba extract (GBE), and Hypericum perforatum extract (HPE), in combination or alone, on the survival and regeneration of axotomized retinal ganglion cells (RGCs) in an optic nerve transection model in adult hamsters. Unilateral transection of the optic nerve was performed to evaluate the effects of herbal extracts on the survival of axotomized RGCs. Effects of the herbal extracts on axonal regeneration of axotomized RGCs, on the other hand, were studied by attaching a peripheral nerve graft onto the transected ocular stump to induce regeneration. Operated animals received daily oral administration of vehicle or herbal extracts (PQE, GBE, and HPE), alone or in combination, for 7 and 21 days, respectively, in the survival and regeneration experiments. Surviving and regenerating RGCs were retrogradely labeled with Fluoro-Gold. The eyes were then enucleated and the retinas were flat-mounted for the counting of the labeled RGCs. Treatment with PQE, GBE and HPE alone failed to offer neuroprotection to injured RGCs. However, treatment with Menta-FX, a mixture of PQE, GBE, and HPE, significantly augmented RGC survival 7 days postaxotomy. Treatment with Menta-FX also induced a significant (87%) increase in the number of regenerating RGCs 21 days after optic nerve transection. This study demonstrates that herbs can act as a potential neuroprotective agent for damaged RGCs. It also suggests that the therapeutic value of herbal remedies can be maximized by the use of mixtures of appropriate herbs.

Postnatal Development of Nicotinamide Adenine Dinucleotide Phosphate-diaphorase-positive Neurons in the Retina of the Golden Hamster

The Journal of Comparative Neurology. May, 2002  |  Pubmed ID: 11954033

The histochemical method was used to investigate the postnatal development of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) -positive neurons in retinas of the golden hamster. NADPH-d-positive neurons were discernible in the retina at postnatal day (P)1. From P4 onward to adulthood, when the retina acquired its laminated characteristics, NADPH-d- positive neurons were observed in the inner nuclear layer (INL) and the ganglion cell layer (GCL). Results showed that NADPH-d-positive neurons in INL and GCL followed different time courses and patterns in their development. NADPH-d-positive neurons in INL underwent a sharp increase from P4 to P8 (3.6-fold), followed by a decrease to 46% of the maximum at P12. This value was maintained relatively constant to the adult level. The mean diameters of NADPH-d-positive neurons in INL, which were smaller than those in the GCL for all ages, increased from P8 to P12 and from P20 to adulthood. As for neurons in the GCL, the increase in cell number was not so apparent for the earlier postnatal days until P20; thereafter, an obvious increase to the adult level was observed. The mean diameters of the NADPH-d-positive cell bodies in the GCL increased with age, except for P16-P20, during which time there was a slight and insignificant decrease. The tendency of changes in cell density was basically similar to that of the total number for both the INL and the GCL. Between P12 and P20, the density distribution map of the NADPH-d-positive neurons underwent dramatic changes: The highest density shifted from the upper central retina at the earlier postnatal days to the lower central retina in the adult. The two waves of increase in NADPH-d-positive neurons coincide with the process of axonal elongation and synaptogenesis and the acquisition of visual function and experience. It is suggested that these NADPH-d-positive neurons are related to these two developmental events.

Expression of TrkA, TrkB, and TrkC in Injured and Regenerating Retinal Ganglion Cells of Adult Rats

Investigative Ophthalmology & Visual Science. Jun, 2002  |  Pubmed ID: 12037005

To investigate changes in percentage of tyrosine kinase (trk)A-, trkB-, and trkC-immunopositive ((+)) retinal ganglion cells (RGCs) at various times after optic nerve (ON) axotomy; the proportion of RGCs regenerating axons into peripheral nerve (PN) grafts that are trkA(+), trkB(+), and trkC(+); whether intravitreal PN-ON implants affect trk immunoreactivity; and the levels of trk mRNAs in ON-injured retinas.

Development of the Regenerative Capacity of Postnatal Axotomized Rat Spinal Motoneurons

Neuroreport. Jun, 2002  |  Pubmed ID: 12060811

The present study examined whether a peripheral nerve (PN) graft can rescue developing motoneurons from degeneration and determined when immature motoneurons begin to express a regenerative capacity. Transplantation of a PN graft was unable to rescue motoneurons from degeneration if spinal root avulsion was performed in animals younger than P14. However, this procedure did enhance motoneuron survival when root avulsion was performed at P14 or later. Immature (P1 or P7) motoneurons were unable to regenerate their axons into the transplanted PN graft following root avulsion, whereas in older animals (P14-P28) motoneurons were able to regenerate axons into the PN graft. The percentage of regenerated motoneurons increased from P21 to P28 and was similar to that of adult animals. Therefore, the regenerative capacity of rat spinal motoneurons first begins at about P14, which seems to be critical.

Total Retinal Nitric Oxide Production is Increased in Intraocular Pressure-elevated Rats

Experimental Eye Research. Oct, 2002  |  Pubmed ID: 12387787

Nitric oxide (NO) is a well-known vaso-dilator but its regulation in the retina is unclear. This study was conducted to quantify total NO production and retinal ganglion cell (RGC) loss in an experimental glaucoma model. Three quarters of the peri-limbal/episcleral drainage vessels and anterior angle (right eyes) of Sprague-Dawley rats were thermally blocked using laser irradiation, while the left eyes served as controls. We measured the intraocular pressure (IOP) of both eyes using a digital tonometer (Tonopen) 21, 28 and 35 days after the laser treatment. After 35 days, we determined the total NO level in retinas and remaining ocular tissues for the laser-treated and control eyes using a spectro-photometric assay. The viable RGC numbers were also determined by counting the cell bodies stained retrogradely by fluoro-gold. The laser treatment significantly increased the IOP 2.0-2.6x throughout the whole periodof measurements (P<0.0001). The mean total RGC number decreased significantly from 98725+/-5383 (+/-S.E. (M.)) to 69276+/-5592, or 29.8% reduction, in the laser-treated eyes after 35 days (P=0.008). The mean total NO level in the laser-treated retina was significantly increased by 2.4x compared with controls (P=0.016), but no significant difference was found in the eyecups (P>0.05). Laser treatment resulted in significant IOP elevation and RGC loss, suggesting that thermal coagulation of the perilimbal region may provide an alternate protocol for glaucoma study. NO level was increased by two-fold in the retina but not in other ocular tissues. Since NO is capable of producing powerful peroxynitrite anions and hydroxyl radicals, elevated level of NO has a potential role in glaucoma.

Retinal Nerve Fiber Layer Measurement of the Hong Kong Chinese Population by Optical Coherence Tomography

Journal of Glaucoma. Dec, 2002  |  Pubmed ID: 12483090

To obtain retinal nerve fiber layer (RNFL) measurements by optical coherence tomography in a local, normal Hong Kong Chinese population and to identify the correlation of the measurement with age cross-sectionally.

Axonal Regeneration of Retinal Ganglion Cells After Optic Nerve Pre-lesions and Attachment of Normal or Pre-degenerated Peripheral Nerve Grafts

Visual Neuroscience. Sep-Oct, 2002  |  Pubmed ID: 12507332

Axonal regeneration of retinal ganglion cells (RGCs) into a normal or pre-degenerated peripheral nerve graft after an optic nerve pre-lesion was investigated. A pre-lesion performed 1-2 weeks before a second lesion has been shown to enhance axonal regeneration in peripheral nerves (PN) but not in optic nerves (ON) in mammals. The lack of such a beneficial pre-lesion effect may be due to the long delay (1-6 weeks) between the two lesions since RGCs and their axons degenerate rapidly 1-2 weeks following axotomy in adult rodents. The present study examined the effects of the proximal and distal ON pre-lesions with a shortened delay (0-8 days) on axonal regeneration of RGCs through a normal or pre-degenerated PN graft. The ON of adult hamsters was transected intraorbitally at 2 mm (proximal lesion) or intracranially at 7 mm (distal lesion) from the optic disc. The pre-lesioned ON was re-transected at 0.5 mm from the disc after 0, 1, 2, 4, or 8 days and a normal or a pre-degenerated PN graft was attached onto the ocular stump. The number of RGCs regenerating their injured axons into the PN graft was estimated by retrograde labeling with FluoroGold 4 weeks after grafting. The number of regenerating RGCs decreased significantly when the delay-time increased in animals with both the ON pre-lesions (proximal or distal) compared to control animals without an ON pre-lesion. The proximal ON pre-lesion significantly reduced the number of regenerating RGCs after a delay of 8 days in comparison with the distal lesion. However, this adverse effect can be overcome, to some degree, by a pre-degenerated PN graft applied 2, 4, or 8 days after the distal ON pre-lesion enhanced more RGCs to regenerate than the normal PN graft. Thus, in order to obtain the highest number of regenerating RGCs, a pre-degenerated PN should be grafted immediately after an ON lesion.

Retinal Nerve Fiber Layer Measurement by Optical Coherence Tomography in Glaucoma Suspects with Short-wavelength Perimetry Abnormalities

Journal of Glaucoma. Feb, 2003  |  Pubmed ID: 12567111

To compare retinal nerve fiber layer (RNFL) measurements in normal and glaucoma subjects with short-wavelength automatic perimetry (SWAP) abnormalities and in chronic primary open-angle glaucoma (CPOAG) patients using optical coherence tomography (OCT).

Intraocular Elevation of Cyclic AMP Potentiates Ciliary Neurotrophic Factor-induced Regeneration of Adult Rat Retinal Ganglion Cell Axons

Molecular and Cellular Neurosciences. Jan, 2003  |  Pubmed ID: 12595238

In vitro, cyclic AMP (cAMP) elevation alters neuronal responsiveness to diffusible growth factors and myelin-associated inhibitory molecules. Here we used an established in vivo model of adult central nervous system injury to investigate the effects of elevated cAMP on neuronal survival and axonal regeneration. We studied the effects of intraocular injections of neurotrophic factors and/or a cAMP analogue (CPT-cAMP) on the regeneration of axotomized rat retinal ganglion cell (RGC) axons into peripheral nerve autografts. Elevation of cAMP alone did not significantly increase RGC survival or the number of regenerating RGCs. Ciliary neurotrophic factor increased RGC viability and axonal regrowth, the latter effect substantially enhanced by coapplication with CPT-cAMP. Under these conditions over 60% of surviving RGCs regenerated their axons. Neurotrophin-4/5 injections also increased RGC viability, but there was reduced long-distance axonal regrowth into grafts, an effect partially ameliorated by cAMP elevation. Thus, cAMP can act cooperatively with appropriate neurotrophic factors to promote axonal regeneration in the injured adult mammalian central nervous system.

Axotomy Induces Cytochrome C Release in Retinal Ganglion Cells

Neuroreport. Feb, 2003  |  Pubmed ID: 12598746

Activation of caspase-3 and -9 has been implicated in the death of axotomized retinal ganglion cells (RGCs). The upstream pathways involved in the activation of these caspases, however, remain unknown. The aim of the current study is to examine the role of cytochrome c release in axotomized RGC death using immuno-histochemistry. We found that while only a low level of cytochrome c immunoreactivity was evident in normal retina, cytochrome c immunoreactivity increased markedly at 1 day post-axotomy, peaked at 3 days post-axotomy, and decreased thereafter. In addition, cytochrome c immunoreactivity localized almost exclusively to RGCs, suggesting that the cytochrome c release observed was injury-related. Our data indicate that cytochrome c release potentially contributes to the death of axotomized RGCs.

Inhibition of Caspases Promotes Long-term Survival and Reinnervation by Axotomized Spinal Motoneurons of Denervated Muscle in Newborn Rats

Experimental Neurology. Jun, 2003  |  Pubmed ID: 12781992

We examined whether (1) a pan-caspase inhibitor, Boc-D-FMK, exerts long-term neuroprotective effects on spinal motoneurons (MNs) after root avulsion in neonatal rats and (2) whether the rescued spinal MNs regenerate their axons into a peripheral nerve (PN) graft and reinnervate a previously denervated target muscle. Eight weeks after root avulsion, 67% of spinal MNs remained in the Boc-D-FMK-treated group, whereas all MNs died in the sham control group. By 12 weeks postinjury, however, all Boc-D-FMK treated MNs died. In the regeneration experiment, a PN graft was implanted at different times after injury. The animals were allowed to survive for 4 weeks following the operation. Without caspase inhibition, MNs did not regenerate at any time point. In animals treated with Ac-DEVD-CHO, a caspase-3-specific inhibitor, and Boc-D-FMK, 44 and 62% of MNs, respectively, were found to regenerate their axons into a PN graft implanted immediately after root avulsion. When the PN graft was implanted 2 weeks after injury, however, MNs failed to regenerate following Ac-DEVD-CHO treatment, whereas 53% of MNs regenerated their axons into the graft after treatment with Boc-D-FMK. No regeneration was observed when a PN graft was implanted later than 2 weeks after injury. In the reinnervation study, injured MNs and the target biceps muscle were reconnected by a PN bridge implanted 2 weeks after root avulsion with administration of Boc-D-FMK. Eight weeks following the operation, 39% of MNs reinnervated the biceps muscle. Morphologically normal synapses and motor endplates were reformed in the muscle fibers. Collectively, these data provide evidence that injured neonatal motoneurons can survive and reinnervate peripheral muscle targets following inhibition of caspases.

Retinal Nerve Fiber Loss Pattern in High-tension Glaucoma by Optical Coherence Tomography

Journal of Glaucoma. Jun, 2003  |  Pubmed ID: 12782845

To identify the pattern of retinal nerve fiber layer thinning in high-tension primary chronic open-angle glaucoma (HT-PCOAG) using optical coherence tomography.

Axonal Regeneration of Clarke's Neurons Beyond the Spinal Cord Injury Scar After Treatment with Chondroitinase ABC

Experimental Neurology. Jul, 2003  |  Pubmed ID: 12821386

We have previously demonstrated that enzymatic digestion of chondroitin sulfate proteoglycan (CSPG) at the scar promotes the axonal regrowth of Clarke's nucleus (CN) neurons into an implanted peripheral nerve graft after hemisection of the spinal cord. The present study examined whether degradation of CSPG using chondroitinase ABC promoted the regeneration of CN neurons through the scar into the rostral spinal cord in neonatal and adult rats. Following hemisection of the spinal cord at T11, either vehicle or chondroitinase ABC was applied onto the lesion site. The postoperative survival periods were 2 and 4 weeks. The regenerated CN neurons were retrogradely labeled by Fluoro-Gold injected at spinal cord level C7. In the sham group, there was no regeneration of injured CN neurons in both neonatal and adult rats. Treatment with 2.5 unit/ml chondroitinase ABC in neonates resulted in 11.8 and 8.3% of the injured CN neurons regenerated into the rostral spinal cord at 2 and 4 weeks, respectively. In adults, 9.4 and 12.3%, at 2 and 4 weeks, respectively, of the injured CN neurons regenerated their axons to the rostral spinal cord. The immunoreactivity for the carbohydrate epitope of CSPG was dramatically decreased around the lesion site after treatment with chondroitinase ABC compared to sham control in both neonatal and adult animals. Our results show that axonal regeneration in the spinal cord can be promoted by degradation of CSPG with chondroitinase ABC. This result further suggests that CSPG is inhibitory to the regeneration of neurons in the spinal cord after traumatic injury.

Inflammatory Response Associated with Axonal Injury to Spinal Motoneurons in Newborn Rats

Developmental Neuroscience. Jan-Feb, 2003  |  Pubmed ID: 12876433

Axonal injury in peripheral nerve results in massive motoneuron loss during development. The purpose of this study was to examine the response of phagocytic populations (brain macrophages, BMOs, versus microglia) after different types of axonal lesions (distal axotomy or avulsion) in newborn rats. The morphology, spatial location and activation state of these inflammatory cells were observed. Following spinal root avulsion, BMOs were signaled rapidly and specifically to the location of dying motoneurons in the spinal cord. A large number of BMOs were observed around the avulsed motoneurons on the lesioned side of the spinal cord 1 day following the lesion. These BMOs were large, round, and intensely stained by both antibodies against ED1 and OX-42. The number of BMOs decreased by 3 days and disappeared by 5 days after injury. At the same time, reactive microglia appeared in the lesioned area and rapidly reached the peak level by the 5th day following avulsion. These reactive microglia were medium in size with retracted cellular processes and were also intensely stained by both ED1 and OX-42 antibodies. The number and staining intensity of reactive microglia declined sharply by day 7 after the lesion. In contrast, after distal axotomy only microglia but not BMOs were observed in the lesioned area. These microglial cells were small in size with long and fine-branched processes. They were ED1-negative but OX-42-positive.

Upstream Signaling Pathways Leading to the Activation of Double-stranded RNA-dependent Serine/threonine Protein Kinase in Beta-amyloid Peptide Neurotoxicity

The Journal of Biological Chemistry. Dec, 2003  |  Pubmed ID: 12975376

One of the hallmarks of Alzheimer's disease is extracellular accumulation of senile plaques composed primarily of aggregated beta-amyloid (Abeta) peptide. Treatment of cultured neurons with Abeta peptide induces neuronal death in which apoptosis is suggested to be one of the mechanisms. We have demonstrated previously that Abeta peptide induces activation of double-stranded RNA-dependent serine/threonine protein kinase (PKR) and phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) in neurons in vitro. Degenerating neurons in brain tissues from Alzheimer's disease patients also displayed high immunoreactivity for phosphorylated PKR and eIF2alpha. Our previous data have also indicated that PKR plays a significant role in mediating Abeta peptide-induced neuronal death, because neurons from PKR knockout mice and neuroblastoma SH-SY5Y cells stably transfected with dominant negative mutant of PKR are less susceptible to Abeta peptide toxicity. Therefore, it is important to understand how PKR is activated by Abeta peptide. We report here that inhibition of caspase-3 activity reduces phosphorylation of PKR and to a certain extent, cleavage of PKR and eIF2alpha in neurons exposed to Abeta peptide. Calcium release from the endoplasmic reticulum and activation of caspase-8 are the upstream signals modulating the caspase-3-mediated activation of PKR by Abeta peptide. Although in other systems HSP90 serves as a repressor for PKR, it is unlikely the candidate for caspase-3 to affect PKR activation in neurons after Abeta peptide exposure. Elucidation of the upstream pathways for PKR activation can help us to understand how this kinase participates in Abeta peptide neurotoxicity and to develop effective neuroprotective strategy.

C-Jun Expression in Surviving and Regenerating Retinal Ganglion Cells: Effects of Intravitreal Neurotrophic Supply

Investigative Ophthalmology & Visual Science. Dec, 2003  |  Pubmed ID: 14638736

To investigate c-jun expression in surviving and axon-regenerating retinal ganglion cells (RGCs) and the effect of intravitreal neurotrophic supply on c-jun expression.

Reduction of Calcium Release from the Endoplasmic Reticulum Could Only Provide Partial Neuroprotection Against Beta-amyloid Peptide Toxicity

Journal of Neurochemistry. Dec, 2003  |  Pubmed ID: 14713297

Beta-amyloid (Abeta) peptide has been suggested to play important roles in the pathogenesis of Alzheimer's disease (AD). Abeta peptide neurotoxicity was shown to induce disturbance of cellular calcium homeostasis. However, whether modulation of calcium release from the endoplasmic reticulum (ER) can protect neurons from Abeta toxicity is not clearly defined. In the present study, Abeta peptide-triggered ER calcium release in primary cortical neurons in culture is modulated by Xestospongin C, 2-aminoethoxydiphenyl borate or FK506. Our results showed that reduction of ER calcium release can partially attenuate Abeta peptide neurotoxicity evaluated by LDH release, caspase-3 activity and quantification of apoptotic cells. While stress signals associated with perturbations of ER functions such as up-regulation of GRP78 was significantly attenuated, other signaling machinery such as activation of caspase-7 transmitting death signals from ER to other organelles could not be altered. We further provide evidence that molecular signaling in mitochondria play also a significant role in determining neuronal apoptosis because Abeta peptide-triggered activation of caspase-9 was not significantly reduced by attenuating ER calcium release. Our results suggest that neuroprotective strategies aiming at reducing Abeta toxicity should include molecular targets linked to ER perturbations associated with ER calcium release as well as mitochondrial stress.

CNTF Promotes Survival of Retinal Ganglion Cells After Induction of Ocular Hypertension in Rats: the Possible Involvement of STAT3 Pathway

The European Journal of Neuroscience. Jan, 2004  |  Pubmed ID: 14725620

We examined the neuroprotective effect of ciliary neurotrophic factor (CNTF) on retinal ganglion cells (RGCs) in a rat glaucoma model with increased intraocular pressure (IOP) and studied the CNTF-mediated activation of Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Elevated IOP was induced by laser photocoagulation of the episcleral and limbal veins. The survival of RGCs was studied using Fluoro-Gold labelled in ocular hypertensive eyes with or without CNTF intravitreal injection. Immunochemical staining and immunoblot analysis for CNTF and phosphorylated STAT3 (pSTAT3) were performed. There was a significant and progressive loss of RGCs in the retinas following the induction of elevated IOP. A single intravitreal injection of 2 microg in 2 microL CNTF significantly protected RGCs up to 4 weeks. pSTAT3 was only transiently expressed in ocular hypertensive eyes. However, in eyes treated with CNTF, pSTAT3 was observed up to 2 weeks after the induction of elevated IOP. In ocular hypertensive eyes, CNTF-positive cells were found in the inner nuclear layer (INL), and there was a transient increase in the pSTAT3 cells in the ganglion cell layer and INL. Immunoblots showed that STAT3 was transiently phosphorylated after IOP increase, but with an injection of CNTF, pSTAT3 protein was observed up to 2 weeks after hypertensive glaucoma induction. Laser-induced chronic ocular hypertension in rats resulted in the death of RGCs and a transient activation of STAT3 in the retina. Intravitreal injection of CNTF showed a significant protection of RGCs, and the JAK-STAT signalling could be one of the important pathways that underlie the mechanism of CNTF neuroprotection in this rat glaucoma model.

Regulation of Caspase Activation in Axotomized Retinal Ganglion Cells

Molecular and Cellular Neurosciences. Mar, 2004  |  Pubmed ID: 15033167

Transection of the optic nerve initiates massive death of retinal ganglion cells (RGCs). Interestingly, despite the severity of the injury, RGC loss was not observed until several days after axotomy. The mechanisms responsible for this initial lack of RGC death remained unknown. In the current study, immunohistochemical analysis revealed that caspases-3 and -9 activation in the RGCs were not detected until day 3 post-axotomy, coinciding with the onset of axotomy-induced RGC loss. Interestingly, elevated Akt phosphorylation was observed in axotomized retinas during the absence of caspase activation. Inhibiting the increase in Akt phosphorylation by intravitreal injection of wortmannin and LY294002, inhibitors of PI3K, resulted in premature nuclear fragmentation, caspases-3 and -9 activation in the ganglion cell layer. Our findings thus indicate that the PI3K/Akt pathway may serve as an endogenous regulator of caspase activation in axotomized RGCs, thereby, contributing to the late onset of RGC death following axotomy.

Modulation of Calcium/calmodulin Kinase-II Provides Partial Neuroprotection Against Beta-amyloid Peptide Toxicity

The European Journal of Neuroscience. Apr, 2004  |  Pubmed ID: 15090032

Beta-amyloid (Abeta) peptide-induced neurotoxicity has been implicated in the pathogenesis of Alzheimer's disease (AD). The exact mechanism by which Abeta peptides trigger neuronal death is not well defined and may be related to an abrupt increase in intracellular calcium, leading to the activation of many pro-apoptotic pathways. While modulation of intracellular calcium increase receives much attention for pharmaceutical intervention, Ca2+-mediated pro-apoptotic signalling pathways have not been systematically studied. We have reported our study on the roles of calcium/calmodulin-dependent protein kinase II (CaMKII) in Abeta peptide neurotoxicity. By treating the primary cortical neurons exposed to Abeta peptides (Abeta(25-35) and Abeta(1-42)) with two selective CaMKII inhibitors, autocamtide-related inhibitory peptide (AIP) and KN93, Abeta peptide neurotoxicity was significantly reduced. Release of LDH and DNA fragmentation/condensation (by DAPI staining) in neurons exposed to Abeta peptides were significantly decreased in the presence of AIP and KN93. While these inhibitors significantly attenuated Abeta peptide-triggered activation of caspase-2 and caspase-3, and AIP significantly decreased the degree of tau phosphorylation of the Abeta peptide-treated neurons at early time, they could elicit partial neuroprotection only. Pharmacological inhibitor targeting calmodulin, W7, did not provide neuroprotection. Morphine, which activates CaMKII via micro receptors, augments Abeta-induced LDH release, caspase-2 and caspase-3 activities and neuronal apoptosis. Taken together, although CaMKII plays a role in Abeta peptide neurotoxicity, pharmacological inhibition cannot afford complete neuroprotection.

Increasing Scans Per Examination Improves the Reproducibility on Retinal Nerve Fiber Layer Measurements by Optical Coherence Tomography

Optometry and Vision Science : Official Publication of the American Academy of Optometry. Apr, 2004  |  Pubmed ID: 15097769

To investigate whether increasing the number of scans per examination would improve the reproducibility of retinal nerve fiber layer (RNFL) measurements by optical coherence tomography (OCT) in healthy and glaucomatous eyes.

Synergistic Effect of Nogo-neutralizing Antibody IN-1 and Ciliary Neurotrophic Factor on Axonal Regeneration in Adult Rodent Visual Systems

Journal of Neurotrauma. May, 2004  |  Pubmed ID: 15165369

The presence of Nogo axon regeneration inhibitory molecules in the central nervous system (CNS) and the counteracting effect of IN-1 antibodies have been widely reported. In this study, we examined the effect of IN-1-producing hybridoma cells on axon regeneration in adult rodent retinal ganglion cells (RGCs) after various types of optic nerve (ON) injury, evaluating therein whether ciliary neurotrophic factor (CNTF) potentiated the effect of IN-1. We found that application of IN-1 alone failed to enhance regeneration of intracranially or intraorbitally transected RGC axons in a peripheral nerve (PN) graft. IN-1 hybridoma cells also failed to significantly promote intraorbitally crushed ON axons to reenter the distal part of the ON. However, a combined application of IN-1 and CNTF had a synergistic effect in both intracranial PN and intraorbital ON crush paradigms. This study suggests that the action of IN-1 antibodies in promoting axon regeneration in the CNS could be more effective when coupled with other appropriate factors.

Retinal Nerve Fiber Loss in High- and Normal-tension Glaucoma by Optical Coherence Tomography

Optometry and Vision Science : Official Publication of the American Academy of Optometry. May, 2004  |  Pubmed ID: 15181362

To compare the pattern of retinal nerve fiber layer (RNFL) damages in high-tension and normal-tension primary chronic open-angle glaucoma using optical coherence tomography (OCT).

Lithium Chloride Reinforces the Regeneration-promoting Effect of Chondroitinase ABC on Rubrospinal Neurons After Spinal Cord Injury

Journal of Neurotrauma. Jul, 2004  |  Pubmed ID: 15307905

After spinal cord injury, enzymatic digestion of chondroitin sulfate proteoglycans promotes axonal regeneration of central nervous system neurons across the lesion scar. We examined whether chondroitinase ABC (ChABC) promotes the axonal regeneration of rubrospinal tract (RST) neurons following injury to the spinal cord. The effect of a GSK-3beta inhibitor, lithium chloride (LiCl), on the regeneration of axotomized RST neurons was also assessed. Adult rats received a unilateral hemisection at the seventh cervical spinal cord segment (C7). Four weeks after different treatments, regeneration of RST axons across the lesion scar was examined by injection of Fluoro-Gold at spinal segment T2, and locomotor recovery was studied by a test of forelimb usage. Injured RST axons did not regenerate spontaneously after spinal cord injury, and intraperitoneal injection of LiCl alone did not promote the regeneration of RST axons. Administration of ChABC at the lesion site enhanced the regeneration of RST axons by 20%. Combined treatment of LiCl together with ChABC significantly increased the regeneration of RST axons to 42%. Animals receiving combined treatment used both forelimbs together more often than animals that received sham or single treatment. Immunoblotting and immunohistochemical analysis revealed that LiCl induced the expression of inactive GSK-3beta as well as the upregulation of Bcl-2 in injured RST neurons. These results indicate that in vivo, LiCl inhibits GSK-3beta and reinforces the regeneration-promoting function of ChABC through a Bcl-2-dependent mechanism. Combined use of LiCl together with ChABC could be a novel treatment for spinal cord injury.

Intravitreal Transplants of Schwann Cells and Fibroblasts Promote the Survival of Axotomized Retinal Ganglion Cells in Rats

Brain Research. Dec, 2004  |  Pubmed ID: 15533316

Schwann cells (SCs) are considered one of the major cellular components to maintain the integrity of the peripheral nervous system (PNS) neurons after injury. Intravitreal transplant of peripheral nerves or Schwann cells has been shown to enhance the regenerative ability of retinal ganglion cells (RGCs). In the present study, we compared the effects of intravitreal transplants of Schwann cells and fibroblasts, two major components of peripheral nerves, on the survival of retinal ganglion cells in adult rats after optic nerve (ON) transection. Purified Schwann cells and fibroblasts from neonatal sciatic nerves were injected into the vitreous body of adult rats. Three days after the injection, the optic nerves were transected intraorbitally. After 1 week or 1 month, surviving retinal ganglion cells were retrogradely labelled with Fluoro-Gold (FG) and the number of surviving retinal ganglion cells was counted. The retinas were further processed for 200-kDa neurofilament RT-97 immunohistochemistry. It was found that intravitreally injected- Schwann cells and -fibroblasts delayed the death of axotomized retinal ganglion cells for 1 week. In addition, in the animal group with 1 month survival time after optic nerve transection, those received a larger number of Schwann cells had more surviving retinal ganglion cells and more profusely ramified axonal processes near the optic disc. These findings reveal that both Schwann cells and fibroblasts isolated from the peripheral nerve can promote retinal ganglion cell survival after optic nerve transection, presumably by secreting neurotrophic factors. In addition, the data also demonstrate that Schwann cells could promote intraretinal axonal sprouting. Our findings demonstrate a remarkable glial source of neurotrophic factors with potential clinical applications, as autologous Schwann cells and fibroblasts can be feasibly obtained from peripheral nerves.

Involvement of CAMP in Neuronal Survival and Axonal Regeneration

Anatomical Science International. Dec, 2004  |  Pubmed ID: 15633459

In vitro, cAMP elevation alters neuronal responsiveness to diffusible growth factors and overcomes myelin-associated inhibitory molecules. Significant advances have been made recently in understanding the role of increases in cAMP in promoting axonal growth. Importantly, it has now been shown that cAMP elevation can promote axonal regeneration and functional recovery after central nervous system injury. Elevation of cAMP can be achieved via either direct application of cAMP analogs or an inhibitor of the enzyme phosphodiesterase that degrades cAMP in vivo. Current information points to a number of protein kinase A-mediated pathways (mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/akt pathway activation and Rho inactivation) underlying cAMP elevation-induced neuronal survival and axonal regeneration.

CNTF and BDNF Have Similar Effects on Retinal Ganglion Cell Survival but Differential Effects on Nitric Oxide Synthase Expression Soon After Optic Nerve Injury

Investigative Ophthalmology & Visual Science. Apr, 2005  |  Pubmed ID: 15790921

To investigate the effect of ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) on retinal ganglion cell (RGC) survival and nitric oxide synthase (NOS) expression in the retina during the early phase of optic nerve (ON) injury, and to examine whether intraperitoneal application of the NOS scavenger nitro-l-arginine (l-NA) could protect the injured RGCs.

Electroacupuncture Provides a New Approach to Neuroprotection in Rats with Induced Glaucoma

Journal of Alternative and Complementary Medicine (New York, N.Y.). Apr, 2005  |  Pubmed ID: 15865499

To investigate, using multifocal electroretinogram (mfERG), the effect of electroacupuncture (EA) on retinal function in rats with experimental glaucoma.

Different Optic Nerve Injury Sites Result in Different Responses of Retinal Ganglion Cells to Brain-derived Neurotrophic Factor but Not Neurotrophin-4/5

Brain Research. Jun, 2005  |  Pubmed ID: 15904902

In this study, we investigated whether brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5) can achieve prolonged protection on retinal ganglion cells (RGCs) and whether site of axon injury modulates RGC response to neurotrophins. Two optic nerve (ON) injury paradigms, proximal and distal transections, were used. Autologous sciatic nerves were grafted onto ON stump in some animals to provide a suitable environment for axons to regrow. Multiple intravitreal injections of saline, BDNF, or NT-4/5 were performed. Immunohistochemistry was used to determine the proportion of RGCs that were expressing trkB. Twenty days after proximal injury, both BDNF and NT-4/5 promoted RGC survival; this protection diminished 30 days after injury. One month after distal injury, BDNF, but not NT-4/5, promoted RGC survival (by 2-fold). No difference in the proportion of trkB expressing RGCs among the viable ones was seen between the two injury models or after BDNF treatment. Interestingly, the mean size of RGC somata was larger after proximal injury than distal injury. This study demonstrates that (1) RGCs respond differently to neurotrophins under different injury conditions, (2) BDNF but not NT-4/5 significantly enhances survival of distally but not proximally injured RGCs over a prolonged period.

Neuroprotective Effects of Anti-aging Oriental Medicine Lycium Barbarum Against Beta-amyloid Peptide Neurotoxicity

Experimental Gerontology. Aug-Sep, 2005  |  Pubmed ID: 16139464

As aged population dramatically increases in these decades, efforts should be made on the intervention for curing age-associated neurodegenerative diseases such as Alzheimer's disease (AD). Natural plant extracts of Lycium barbarum are well-known to exhibit anti-aging effects. We therefore hypothesized that they exhibit neuroprotective effects against toxins in aging-related neurodegenerative diseases. In this study, we aimed to investigate whether extracts from L. barbarum have neuroprotective effects against toxicity of fibrillar Abeta(1-42) and Abeta(25-35) fragments. Primary rat cortical neurons exposed to Abeta peptides resulted in apoptosis and necrosis. Pre-treatment with extract isolated from L. barbarum significantly reduced the release of lactate dehydrogenase (LDH). In addition, it attenuated Abeta peptide-activated caspases-3-like activity. The extract elicited a typical dose-dependent neuroprotective effect. Effective dosage of this extract was wider than that of a well-known western neuroprotective medicine lithium chloride (LiCl). We have further examined the underlying mechanisms of the neuroprotective effects. In agreement with other laboratories, Abeta peptides induce a rapid activation of c-Jun N-terminal kinase (JNK) by phosphorylation. Pre-treatment of aqueous extract markedly reduced the phosphorylation of JNK-1 (Thr183/Tyr185) and its substrates c-Jun-I (Ser 73) and c-Jun-II (Ser 63). Taken together, we have proved our hypothesis by showing neuroprotective effects of the extract from L. barbarum. Study on anti-aging herbal medicine like L. barbarum may open a new therapeutic window for the prevention of AD.

Transgenic Mice Expressing Cre-recombinase Specifically in Retinal Rod Bipolar Neurons

Investigative Ophthalmology & Visual Science. Oct, 2005  |  Pubmed ID: 16186328

To establish a transgenic mouse line that expresses Cre-recombinase in retinal rod bipolar cells for the generation of rod bipolar cell-specific knockout mutants.

Aldose Reductase Deficiency Prevents Diabetes-induced Blood-retinal Barrier Breakdown, Apoptosis, and Glial Reactivation in the Retina of Db/db Mice

Diabetes. Nov, 2005  |  Pubmed ID: 16249434

In 15-month-old db/db mice, signs of diabetic retinopathy, including blood-retinal barrier breakdown, loss of pericytes, neuro-retinal apoptosis, glial reactivation, and proliferation of blood vessels, were evident. These changes in the diabetic retina were associated with increased expression of aldose reductase (AR). To further understand the role of AR in the pathogenesis of diabetic retinopathy, we generated db/db mice with an AR null mutation (AR-/- db/db). AR deficiency led to fewer retinal blood vessels with IgG leakage, suggesting that AR may contribute to blood-retinal barrier breakdown. AR deficiency also prevented diabetes-induced reduction of platelet/endothelial cell adhesion molecule-1 expression and increased expression of vascular endothelial growth factor, which may have contributed to blood-retinal barrier breakdown. In addition, long-term diabetes-induced neuro-retinal stress and apoptosis and proliferation of blood vessels were less prominent in AR-/- db/db mice. These findings indicate that AR is responsible for the early events in the pathogenesis of diabetic retinopathy, leading to a cascade of retinal lesions, including blood-retinal barrier breakdown, loss of pericytes, neuro-retinal apoptosis, glial reactivation, and neovascularization.

Developmental Changes of Nitric Oxide Synthase Expression in the Rat Hypothalamoneurohypophyseal System

The Anatomical Record. Part A, Discoveries in Molecular, Cellular, and Evolutionary Biology. Jan, 2006  |  Pubmed ID: 16342209

The present study investigated the immunohistochemical localization of neuronal nitric oxide synthase (nNOS) in the hypothalamoneurohypophyseal system (HNS) of the developing rats on postnatal day 1 (PN1), 7 (PN7), 14 (PN14), 21 (PN21), and the adult rats. The nNOS-positive neurons were not discernable in the supraoptic nucleus (SON), the paraventricular nucleus (PVN), and the median eminence (ME) at PN1 and PN7. A few neurons positive for nNOS were first detected at PN14. At PN21, the nNOS-positive cells in SON and PVN rapidly increased in number. The pattern of nNOS expression at this stage approached that of the adult. Moreover, the increase of nNOS expression in the SON and PVN during the postnatal period was accompanied by the maturation of arginine vasopressin (AVP) and oxytocin (OT) neurons as indicated by the number and size of OT or AVP neurons in the SON and PVN. The patterns of AVP versus OT expression also reached that of the adult by the end of the third postnatal week. The time course of the change in nNOS expression coincided with the maturation of AVP and OT neurons in the HNS and suggested that NO synthesized by conversion of NOS is involved in the modulation of activity of neurons in the SON and PVN of the HNS.

Light Delays Synaptic Deafferentation and Potentiates the Survival of Axotomized Retinal Ganglion Cells

Neuroscience Letters. Mar, 2006  |  Pubmed ID: 16352397

Knowledge of the cellular mechanism underlying the therapeutic effect of stimulation and the optimal doses of such stimulation to maximize neuronal recovery is essential to guide clinical practice in neural rehabilitation. Using hamsters, we transected the optic nerve to demonstrate how light stimulation affects neuronal recovery. The c-fos protein was used as a neuronal connectivity marker. Here we show that: (a) in addition to cell death, a population of cells undergoes synaptic deafferentation and (b) light stimulation delays cell death and deafferentation. Among the three rearing conditions studied (6:18LD, 12:12LD, and 18:6LD), the 12:12LD condition appears to be the one achieving the optimal therapeutic effect. This study provides a solid base in the understanding of the neuroanatomical changes after traumatic brain injury and the need to establish an optimal level and timing for the environmental stimulation.

Beta-amyloid Peptides Induces Neuronal Apoptosis Via a Mechanism Independent of Unfolded Protein Responses

Apoptosis : an International Journal on Programmed Cell Death. May, 2006  |  Pubmed ID: 16532272

Accumulation of beta-amyloid (Abeta) peptides in senile plaques is one of the pathological hallmarks in Alzheimer's disease (AD), which can trigger apoptosis. We have previously demonstrated that Abeta triggered calcium release from the ER. Depletion of ER Ca(2+) ions has been reported leading to unfolded protein responses (UPR). While hypothesis has been made about UPR and neurodegeneration in AD, little is known about the effects of extracellular accumulation of Abeta on UPR. We have shown previously that activation of PKR in Abeta-triggered apoptosis. Since UPR can trigger PKR, our study aims to elucidate whether extracellular accumulation of Abeta peptides induce UPR in cultured neurons. Our results showed that Abeta could not trigger UPR signalings including phosphorylation of PERK, alternative cleavage of xbp-1 mRNA and induction of transcription of xbp-1 and Gadd153. Taken together, our results suggest that extracellular accumulation of Abeta peptides induce apoptosis via a mechanism independent of UPR.

Nano Neuro Knitting: Peptide Nanofiber Scaffold for Brain Repair and Axon Regeneration with Functional Return of Vision

Proceedings of the National Academy of Sciences of the United States of America. Mar, 2006  |  Pubmed ID: 16549776

Nanotechnology is often associated with materials fabrication, microelectronics, and microfluidics. Until now, the use of nanotechnology and molecular self assembly in biomedicine to repair injured brain structures has not been explored. To achieve axonal regeneration after injury in the CNS, several formidable barriers must be overcome, such as scar tissue formation after tissue injury, gaps in nervous tissue formed during phagocytosis of dying cells after injury, and the failure of many adult neurons to initiate axonal extension. Using the mammalian visual system as a model, we report that a designed self-assembling peptide nanofiber scaffold creates a permissive environment for axons not only to regenerate through the site of an acute injury but also to knit the brain tissue together. In experiments using a severed optic tract in the hamster, we show that regenerated axons reconnect to target tissues with sufficient density to promote functional return of vision, as evidenced by visually elicited orienting behavior. The peptide nanofiber scaffold not only represents a previously undiscovered nanobiomedical technology for tissue repair and restoration but also raises the possibility of effective treatment of CNS and other tissue or organ trauma.

Age-related Reexpression of P75 in Axotomized Motoneurons

Neuroreport. May, 2006  |  Pubmed ID: 16641674

p75 was immunohistochemically identified in spinal motoneurons in immature and adult rats after either distal peripheral axotomy or root avulsion. Few or no p75 positive motoneurons were observed after distal axotomy in animals at the age of postnatal day 1 and postnatal day 7, whereas the injury induced marked neuronal death. Motoneurons reexpressed p75 from the end of the second postnatal week to adulthood in response to distal axotomy, whereas most motoneurons survived after the injury. On the other hand, root avulsion in animals of all ages did not cause significant p75 expression in avulsed motoneurons where most motoneurons died ultimately. The potential role of such reexpression in motoneuron protection is discussed.

Cytoprotective Effects of Lycium Barbarum Against Reducing Stress on Endoplasmic Reticulum

International Journal of Molecular Medicine. Jun, 2006  |  Pubmed ID: 16685430

Chinese medicinal herbs have been consumed for thousands of years for the purpose of healthy aging. Lycium barbarum is valued in Chinese culture for its benefits to anti-aging, vision, kidney and liver. Recent studies showed that extracts from L. barbarum possess biological activities including anti-aging, anti-tumor, immune-stimulatory and cytoprotection. Most of these studies emphasized that the protective function of L. barbarum is due to its anti-oxidative effects. We have previously demonstrated that extract from L. barbarum can protect neurons against beta-amyloid (Abeta) peptide-induced apoptosis. Since Abeta toxicity may be mediated via oxidative stress, it is still unclear whether the extract from L. barbarum is a simple anti-oxidant exhibiting cytoprotective effects. We hypothesized that extract from L. barbarum is not simply an anti-oxidant in order to function as a neuroprotective agent. The aim of this study is to investigate whether the extract from L. barbarum (LBG) protect neurons via mechanisms independent of anti-oxidative effects. Using a reducing agent, dithiothreitol (DTT), we found that LBG exhibits cytoprotective effects against reducing stress by lowering the DTT-induced LDH release and caspase-3 activity. DTT can trigger endoplasmic reticulum (ER) stress leading to PKR-like ER kinase (PERK) activation. We also showed that LBG attenuates DTT-induced PERK phosphorylation. The extract from L. barbarum is not simply an anti-oxidant; it can also exhibit cytoprotective effects against reducing stress by DTT.

Characterization and Localization of the Supraorbital and Frontal Exits of the Supraorbital Nerve in Chinese: an Anatomic Study

Ophthalmic Plastic and Reconstructive Surgery. May-Jun, 2006  |  Pubmed ID: 16714932

To elucidate the characteristics and location of the supraorbital and frontal exits of the supraorbital nerve in Chinese skulls and to compare these findings with other ethnic populations.

Melanopsin-expressing Retinal Ganglion Cells Are More Injury-resistant in a Chronic Ocular Hypertension Model

Investigative Ophthalmology & Visual Science. Jul, 2006  |  Pubmed ID: 16799038

To investigate the survival of melanopsin-expressing retinal ganglion cells (mRGCs) after the induction of chronic ocular hypertension.

Graded Ephrin-A2 Expression in the Developing Hamster Superior Colliculus

Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale. Aug, 2006  |  Pubmed ID: 16850319

During development, ephrin gradients guide retinal ganglion cell axons to their appropriate topographic locations in the superior colliculus (SC). Expression of ephrin-A2, assessed immunohistochemically in the developing hamster SC, revealed a rostral(low) to caudal (high) gradient that is most prominent at postnatal days P4 and P7 when topography is established. Double-labelling immunohistochemistry for ephrin-A2 and cell specific markers revealed that ephrin-A2 is expressed exclusively by a subset of neurons. The expression pattern has implications for mechanisms underlying establishment of topography during development and following injury.

Expression of Nicotinamide Adenine Dinucleotide Phosphate-diaphorase in the Retina of Postnatal Golden Hamsters Deprived of Light Stimulation

Neuroscience Letters. Sep, 2006  |  Pubmed ID: 16854523

Nicotinamide Adenine Dinucleotide Phosphate-Diaphorase (NADPH-d) expressing neurons in the retina of golden hamsters have been identified to be a subset of amacrine cells that provide a major source of Nitric Oxide (NO) in retina. This subset of amacrine cells in mouse retina was recently proved to contain the circadian clock gene Per1 (D.Q. Zhang, T. Zhou, G.X. Ruan, D.G. McMahon, Circadian rhythm of Period 1 clock gene expression in NOS amacrine cells of the mouse retina, Brain Res., 1050 (2005) 101-109). However, it remains unknown whether these clock-related NADPH-d amacrine cells can be regulated by light stimulation and thus synchronized to ambient day/night cycle. A previous study has reported that NADPH-d expressing amacrine cells in postnatal hamsters exhibited a surge after eye-opening (D. Tay, Y.C. Diao, Y.M. Xiao, K.F. So, Postnatal development of nicotinamide adenine dinucleotide phosphate-diaphorase-positive neurons in the retina of the golden hamster, J. Comp. Neurol., 446 (2002) 342-348) suggesting a possible effect of light on the NADPH-d amacrine cells. In order to further reveal the relationship between NADPH-d amacrine cells and light stimulation, the present study focuses on the changes of the expression of NADPH-d in the retina of postnatal hamsters reared in completely deprived light conditions. Prior to eye opening, P12 hamster pups were subjected to either bilateral eyelid suturing or dark rearing. On P28 a subgroup of light deprived hamsters was returned to lighting conditions and the expression of NADPH-d activities in the retina was assessed. In hamsters reared in the 12:12 light-dark cycle, the number of NADPH-d amacrine cells in the ganglion cell layer (GCL) increased right after eye-opening and reached the adult level gradually. However, hamsters subjected to both bilateral eyelid suturing and dark rearing, the number of NADPH-d amacrine cells in GCL was maintained at a low level but increased again upon returning to the 12:12 light-dark condition. In contrast, the number of NADPH-d expressing amacrine cells in the inner nuclear layer (INL) remained low and unaltered regardless of the lighting environment. This study demonstrates that there are two subpopulations of NADPH-d expressing amacrine cells with respect to different locations in the retina of hamsters. Different from those in INL, the NADPH-d amacrine cells in GCL of postnatal hamsters are dependent on the lighting environment implicating that these clock-related amacrine cells and the production of NO might be under a modulation of light stimulation.

Changes of Retinal Functions Following the Induction of Ocular Hypertension in Rats Using Argon Laser Photocoagulation

Clinical & Experimental Ophthalmology. Aug, 2006  |  Pubmed ID: 16925706

Electroretinography (ERG) provides a longitudinal monitoring of pathological changes in retina. Scotopic threshold response (STR) of ERG was shown to reflect inner retinal activity and is particularly useful in the evaluation of inner retinal changes in ocular hypertension models. Recently, STR was demonstrated to be attenuated after the induction of ocular hypertension using injection of hypertonic saline into episcleral veins which indicates an impairment of retinal function. However, little is known on the changes of retinal function in an ocular hypertension model induced by laser photocoagulation at episcleral veins and limbal veins.

The Response of Magnocellular Neurons of the Hypothalamo-neurohyphyseal System to Hypophysectomy, Nitric Oxide Synthase Expression As Well As Survival and Regeneration in Developing Vs. Adult Rats

Brain Research. Oct, 2006  |  Pubmed ID: 16949057

This study examined the age-related changes in nitric oxide synthase immunoreactivity (NOS-IR), survival and regeneration of magnocellular neurons in the hypothalamo-neurohypophyseal system (HNS) in rats following hypophysectomy. In adult animal, hypophysectomy induced a significant increase in NOS-IR in the supraoptic (SON), paraventricular nuclei (PVN) and median eminence (ME) by 3 days post-lesion. NOS sustained an increased level until 2 weeks after hypophysectomy and then returned to normal control level. In contrast, at postnatal day 7 (PN7), no obvious increase in NOS-IR was observed in the SON, PVN and ME following the injury compared with age-matched controls. At PN14, the same injury induced an increase in NOS-IR in SON, PVN and ME but the increase was more transient with peak NOS-IR at 3 days and returning to the corresponding control level at 1 week after hypophysectomy. In contrast to a striking age-dependent alteration in NOS-IR in the SON and PVN, hypophysectomy induced substantial degeneration of arginine vasopressin (AVP) and oxytocin (OT) neurons in the SON and PVN in both immature and adult rats and there was no obvious difference in neuronal survival after the same injury among these three groups of different ages by quantitative analysis. Following hypophysectomy, a large number of fibers were observed in the contact zone of the median eminence and the adjacent lumen of the third cerebral ventricle (V3) in adult rats, whereas few fibers could be found in the lumen of the V3 in the immature rats after the same injury. Relationships between NOS induction and magnocellular neuronal survival and regeneration were discussed.

A Suprachiasmatic Nucleus Projecting Retinal Ganglion Cell Exhibits an Unusually Large Dendritic Field in the Hamster

Neuroreport. Oct, 2006  |  Pubmed ID: 16957590

The majority of retinal ganglion cells innervating the suprachiasmatic nucleus are intrinsically light sensitive, while the rest are conventional ganglion cells that collect inputs through conventional photoreceptors. Here we report a rarely encountered ganglion cell that had a dendritic field covering approximately 14.4% of retinal surface and its processes ramified in both the inner and the outer plexiform layers. This cell could have a potential role in detecting luminance changes over a large area of retinal surface.

LINGO-1 Antagonist Promotes Functional Recovery and Axonal Sprouting After Spinal Cord Injury

Molecular and Cellular Neurosciences. Nov, 2006  |  Pubmed ID: 17011208

LINGO-1 is a CNS-specific protein and a functional component of the NgR1/p75/LINGO-1 and NgR1/TAJ(TROY)/LINGO-1 signaling complexes that mediate inhibition of axonal outgrowth. These receptor complexes mediate the axonal growth inhibitory effects of Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (OMgp) via RhoA activation. Soluble LINGO-1 (LINGO-1-Fc), which acts as an antagonist of these pathways by blocking LINGO-1 binding to NgR1, was administered to rats after dorsal or lateral hemisection of the spinal cord. LINGO-1-Fc treatment significantly improved functional recovery, promoted axonal sprouting and decreased RhoA activation and increased oligodendrocyte and neuronal survival after either rubrospinal or corticospinal tract transection. These experiments demonstrate an important role for LINGO-1 in modulating axonal outgrowth in vivo and that treatment with LINGO-1-Fc can significantly enhance recovery after spinal cord injury.

Nano Hemostat Solution: Immediate Hemostasis at the Nanoscale

Nanomedicine : Nanotechnology, Biology, and Medicine. Dec, 2006  |  Pubmed ID: 17292144

Hemostasis is a major problem in surgical procedures and after major trauma. There are few effective methods to stop bleeding without causing secondary damage. We used a self-assembling peptide that establishes a nanofiber barrier to achieve complete hemostasis immediately when applied directly to a wound in the brain, spinal cord, femoral artery, liver, or skin of mammals. This novel therapy stops bleeding without the use of pressure, cauterization, vasoconstriction, coagulation, or cross-linked adhesives. The self-assembling solution is nontoxic and nonimmunogenic, and the breakdown products are amino acids, which are tissue building blocks that can be used to repair the site of injury. Here we report the first use of nanotechnology to achieve complete hemostasis in less than 15 seconds, which could fundamentally change how much blood is needed during surgery of the future.

Corticosteroid Decreases Subventricular Zone Cell Proliferation, Which Could Be Reversed by Paroxetine

Restorative Neurology and Neuroscience. 2007  |  Pubmed ID: 17473392

Major depressive disorder is often associated with elevated glucocorticoid levels, which in turn suppress cell proliferation and neurogenesis in the hippocampus. Increasing evidence supports that antidepressants induce hippocampal neurogenesis and this induces speculation that decrease in hippocampal neurogenesis has causal relationship with depression. There is, however, a lack of information about neurogenic effects of antidepressants on the subventricular zone, which is another CNS region with continuous neurogenesis throughout adulthood. In the present study, we investigated whether corticosterone and the SSRI paroxetine, have effects on SVZ cell proliferation.

New Polysaccharide from Nerium Indicum Protects Neurons Via Stress Kinase Signaling Pathway

Brain Research. Jun, 2007  |  Pubmed ID: 17475226

Most of the polysaccharides purified from Chinese medicinal herbs showed anti-tumor and immune-stimulating effects. However, little is known about their effects on neuroprotection. Our previous study has demonstrated that polysaccharides (J2, J3 and J4) isolated from the flowers of Nerium indicum (Oleander) exert partial protection in cortical neurons stressed by beta-amyloid (Abeta) peptides or deprivation of nutrition from serum. In this study, we have isolated and characterized a new polysaccharide from the flowers of N. indicum (named as J6) and aimed to investigate its neuroprotective effects against Abeta-induced apoptosis. Pretreatment of the polysaccharide J6 significantly decreased the activity of caspase-3 as well as the cytotoxicity triggered by Abeta peptides in a dose-dependent manner. In contrast to the activation of survival signaling such as Akt found in J2, J3 and J4 fractions, neuroprotective effects of J6 markedly inhibited Abeta peptide-stimulated phosphorylation of c-Jun N-terminal kinase (JNK-1) as determined by Western blot analysis. Taken together, the polysaccharide J6 isolated from the flowers of N. indicum can serve as potential neuroprotective agent against neuronal death in Alzheimer's disease and the neuroprotective mechanism may primarily rely on inactivation of JNK signaling pathway.

Characterizing the Neuroprotective Effects of Alkaline Extract of Lycium Barbarum on Beta-amyloid Peptide Neurotoxicity

Brain Research. Jul, 2007  |  Pubmed ID: 17568570

Lycium barbarum is an oriental medicinal herb that has long been used for its anti-aging and cell-protective properties. Previous studies have shown that aqueous extracts from L. barbarum exhibit neuroprotection via inhibiting pro-apoptotic signaling pathways. Other active components can also be accomplished by novel alkaline extraction method, which may give different profiles of water-soluble components. We hypothesize that another active component obtained by alkaline extraction method exerts different biological mechanisms to protect neurons. In this study, we aim to examine the neuroprotective effects from the alkaline extract of L. barbarum, namely LBB, to attenuate beta-amyloid (Abeta) peptide neurotoxicity. Primary cortical neurons were exposed to Abeta-peptides inducing apoptosis and neuronal cell death. Pretreatment of LBB significantly reduced the level of lactate dehydrogenase (LDH) release and the activity of caspase-3 triggered by Abeta. "Wash-out" procedures did not reduce its neuroprotective effects, suggesting that LBB may not bind directly to Abeta. We have further isolated three subfractions from LBB, namely LBB-0, LBB-I and LBB-II. LBB-I and LBB-II showed differential neuroprotective effects. Western blot analysis demonstrated that LBB-I and LBB-II markedly enhanced the phosphorylation of Akt. Taken together, our results suggested that the glycoconjugate isolated from novel alkaline extraction method can open up a new avenue for drug discovery in neurodegenerative diseases.

A Subpopulation of Reactive Astrocytes at Affected Neuronal Perikarya After Hypophysectomy in Adult Rats

Brain Research. Jul, 2007  |  Pubmed ID: 17573051

Intermediate filaments (IFs) of nestin and vimentin are expressed in immature astrocytes. In this study, we examined the re-expression of these early glial traits in rat reactive astrocytes in affected neuronal perikarya in supraoptic (SON) and paraventricular (PVN) nuclei induced by hypophysectomy. Double-labeling immunofluorescence confocal laser microscopy demonstrated that by 7 days post-lesion, both nestin and vimentin were present intensely in hypertrophied GFAP-IR reactive astrocytes in the area of hypophysectomized magnocellular neurons in SON and PVN, while nestin and vimentin are absent in the normal or sham-operated animals. As the gliotic reaction progressed, the morphology of nestin or vimentin-positive reactive astrocytes in SON but not PVN changed from stellate form at 7 days to thin and elongated shape, morphologically compatible with radial glia during development, at 14 days post-lesion. By 28 days post-lesion, while vimentin-IR persisted in reactive astrocytes in SON and PVN, nestin-IR could hardly be detected. The spatiotemporal pattern of nestin-IR and/or vimentin-IR in reactive astrocytes suggests astrocytes attempt to revert to a more primitive glia form indicated by changes in morphology and phenotype following hypophysectomy, which may contribute to neuronal trophism and plasticity in the lesioned HNS favoring neuronal maintenance and fiber outgrowth.

Characterization of the Effects of Anti-aging Medicine Fructus Lycii on Beta-amyloid Peptide Neurotoxicity

International Journal of Molecular Medicine. Aug, 2007  |  Pubmed ID: 17611646

Alzheimer's disease (AD) is an age-related neurodegenerative disease. There are increasing lines of evidence showing that the molecular signaling pathways in aged cells are altered so that cells are susceptible to injury. We and other laboratories have demonstrated the significant involvement of double-stranded RNA-dependent protein kinase (PKR) in beta-amyloid (A beta) peptide neurotoxicity and in AD. Fructus lycii (the fruit of Lycium barbarum) has long been used in oriental medicine as an anti-aging agent. Our previous studies demonstrated that the aqueous extract isolated from L. barbarum exhibited significant protection on cultured neurons against harmful chemical toxins such as A beta and dithiothreitol. We also showed that the polysaccharide-containing extract (LBP) from L. barbarum exhibited neuroprotective effects in the retina against ocular hypertension in a laser-induced glaucoma animal model. In this study, we aimed to investigate whether LBP can elicit neuroprotection to neurons stressed by A beta peptides. Furthermore, we planned to isolate and identify the neuroprotective agent from LBP using chromatographic methods. Our results showed that pretreatment of LBP effectively protected neurons against A beta-induced apoptosis by reducing the activity of both caspase-3 and -2, but not caspase-8 and -9. A new arabinogalactan-protein (LBP-III) was isolated from LBP and attenuated A beta peptide-activated caspase-3-like activity. LBP-III markedly reduced the phosphorylation of PKR triggered by A beta peptide. Since the phosphorylation state of PKR increased with age, reduction of its phosphorylation triggered by A beta peptide may implicate that LBP-III from Fructus lycii is a potential neuroprotective agent in AD. As herbal medicine has received increasing attention for the treatment of AD, our study will open a window for the development of a neuroprotective agent for anti-aging from Chinese medicine.

Modulation of the Suppressive Effect of Corticosterone on Adult Rat Hippocampal Cell Proliferation by Paroxetine

Neuroscience Bulletin. May, 2007  |  Pubmed ID: 17612590

The literature has shown that cognitive and emotional changes may occur after chronic treatment with glucocorticoids. This might be caused by the suppressive effect of glucocorticoids on hippocampal neurogenesis and cell proliferation. Paroxetine, a selective serotonin reuptake transporter, is a commonly used antidepressant for alleviation of signs and symptoms of clinical depression. It was discovered to promote hippocampal neurogenesis in the past few years and we wanted to investigate its interaction with glucocorticoid in this study.

Differential Activation of C-fos Immunoreactivity After Hypophysectomy in Developing and Adult Rats

Anatomical Record (Hoboken, N.J. : 2007). Sep, 2007  |  Pubmed ID: 17661378

The aim of the present study is to compare c-fos expression in identified hypothalamic vasopressin (AVP) and oxytocin (OT) neurons in developing (PN7 and PN14) and adult rats following hypophysectomy using dual-labeled immunostaining. Our results showed that hypophysectomy induced c-fos expression in supraoptic (SON) and paraventricular (PVN) nuclei in both the developing and adult rats. Few or no positive cells were observed in the same nuclei in sham-operated animals. Quantitative analysis for c-fos and either of the above named neuropeptides revealed that almost all AVP and OT neurons in the adult and PN14 groups expressed c-fos in response to hypophysectomy. In PN7, hypophysectomy also induced all AVP neurons to express c-fos in SON and PVN. However, few OT neurons in the SON and PVN produced c-fos after hypophysectomy. In addition, the time course of c-fos expression was different in the developing and adult rats after hypophysectomy. The c-fos expression in the developing rats exhibited a more prolonged induction in which staining for c-fos persisted for at least 3 days after hypophysectomy compared with that in the adult in which c-fos immunoreactivity disappeared within 24 hr post-lesion. This study demonstrates that c-fos expression after hypophysectomy is regulated differently during development.

Chemotactic Effect of Ciliary Neurotrophic Factor on Macrophages in Retinal Ganglion Cell Survival and Axonal Regeneration

Investigative Ophthalmology & Visual Science. Sep, 2007  |  Pubmed ID: 17724215

To examine whether ciliary neurotrophic factor (CNTF) has a chemotactic effect on macrophages and whether macrophages are involved in CNTF-induced retinal ganglion cell (RGC) survival and axonal regeneration after optic nerve (ON) injury.

Gene Deletion and Pharmacological Inhibition of Aldose Reductase Protect Against Retinal Ischemic Injury

Experimental Eye Research. Nov, 2007  |  Pubmed ID: 17727843

Retinal ischemic injury is common in patients with diabetes, atherosclerosis, hypertension, transient ischemia attack and amaurosis fugax. Previously, signs of ischemic stress, such as pericyte loss, blood-retinal barrier breakdown and neovascularization, which can lead to occlusion of retinal vessels, have been prevented in diabetic db/db mice with aldose reductase (AR) null mutation. To determine the role in retinal ischemic injury of AR and sorbitol dehydrogenase (SDH), the first and second enzymes in the polyol pathway, mice with deletion of AR (AR(-/-)) or SDH-mutation (SDH(-/-)), or C57BL/6N mice treated with AR or SDH inhibitors were subjected to transient retinal artery occlusion (2h of occlusion and 22h of reperfusion) by the intraluminal suture method. Neuronal loss and edema observed in wildtype (AR(+/+)) retinas after transient ischemia were prevented in the retinas of AR(-/-) mice or C57BL/6N mice treated with an AR inhibitor, Fidarestat. Fewer TUNEL-positive cells and smaller accumulations of nitrotyrosine and poly(ADP-ribose) were also observed in the retinas of AR(-/-) mice. However, SDH(-/-) mice and C57BL/6N mice treated with SDH inhibitor, CP-470,711, were not protected against ischemia-induced retinal damage. Taken together, AR contributes to retinal ischemic injury through increased edema and free radical accumulation. Therefore, AR inhibition should be considered for the treatment of retinal ischemic injury often observed in diabetic patients.

LINGO-1 Antagonist Promotes Spinal Cord Remyelination and Axonal Integrity in MOG-induced Experimental Autoimmune Encephalomyelitis

Nature Medicine. Oct, 2007  |  Pubmed ID: 17906634

Demyelinating diseases, such as multiple sclerosis, are characterized by the loss of the myelin sheath around neurons, owing to inflammation and gliosis in the central nervous system (CNS). Current treatments therefore target anti-inflammatory mechanisms to impede or slow disease progression. The identification of a means to enhance axon myelination would present new therapeutic approaches to inhibit and possibly reverse disease progression. Previously, LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) has been identified as an in vitro and in vivo negative regulator of oligodendrocyte differentiation and myelination. Here we show that loss of LINGO-1 function by Lingo1 gene knockout or by treatment with an antibody antagonist of LINGO-1 function leads to functional recovery from experimental autoimmune encephalomyelitis. This is reflected biologically by improved axonal integrity, as confirmed by magnetic resonance diffusion tensor imaging, and by newly formed myelin sheaths, as determined by electron microscopy. Antagonism of LINGO-1 or its pathway is therefore a promising approach for the treatment of demyelinating diseases of the CNS.

Reknitting the Injured Spinal Cord by Self-assembling Peptide Nanofiber Scaffold

Nanomedicine : Nanotechnology, Biology, and Medicine. Dec, 2007  |  Pubmed ID: 17964861

In traumatic spinal cord injury, loss of neurological function is due to the inability of damaged axons to regenerate across large, cystic cavities. It has recently been demonstrated that a self-assembled nanofiber scaffold (SAPNS) could repair the injured optical pathway and restore visual function. To demonstrate the possibility of using it to repair spinal cord injury, transplanted neural progenitor cells and Schwann cells were isolated from green fluorescent protein-transgenic rats, cultured within SAPNS, and then transplanted into the transected dorsal column of spinal cord of rats. Here we report the use of SAPNS to bridge the injured spinal cord of rats, demonstrating robust migration of host cells, growth of blood vessels, and axons into the scaffolds, indicating that SAPNS provides a true three-dimensional environment for the migration of living cells.

Evaluation of the Visual System in a Rat Model of Chronic Glaucoma Using Manganese-enhanced Magnetic Resonance Imaging

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2007  |  Pubmed ID: 18001890

This study aims to employ in vivo manganese-enchanced MRI (MEMRI) to evaluate dynamically the Mn(2+) enhancements along the visual pathway following an induction of ocular hypertension in a rat model of chronic glaucoma. Results showed an accumulation of Mn(2+) ions in the vitreous humor of the glaucomatous eye, with no statistical changes in the total retinal thickness but a possible occlusion of the ions at the optic nerve head. Meanwhile, there was a reduction in Mn(2+) transport in the glaucomatous optic nerve in the later stage of our model. Fewer enhancements in the visual cortex projected from the glaucomatous eye were also detectable. These may help understand the disease mechanisms, monitor the effect of drug interventions to glaucoma models, and complement the conventional techniques in examining the visual components.

Diffusion Tensor MR Study of Optic Nerve Degeneration in Glaucoma

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2007  |  Pubmed ID: 18002956

Axonal degeneration has been known to occur in the optic nerve (ON) of rat glaucoma model. Recently, quantitative diffusion tensor imaging (DTI) has been developed to investigate various white matter diseases in vivo. In this study, longitudinal DTI was thus employed to study such animal model in the present study. The results showed that radial diffusivity (lambda) and fractional anisotropy (FA) of the glaucomatous ON (gON) was increasing and decreasing respectively with time after glaucoma induction, whereas there was no significant change in the axial diffusivity (lambda//). Supported by the histological staining of the ON, such changes in the two DTI-derived parameters were attributed to the 10% decrease in the axonal density of the gON as compared to nON. It was shown for the first time that DTI can be sensitive enough to detect axonal degeneration in rat glaucoma model. DTI therefore holds promise for reliable diagnoses and assessment of the glaucoma disease in human upon careful interpretation of the DTI-derived directional diffusivities.

Neuroprotective Effects of Lycium Barbarum Lynn on Protecting Retinal Ganglion Cells in an Ocular Hypertension Model of Glaucoma

Experimental Neurology. Jan, 2007  |  Pubmed ID: 17045262

Glaucoma is one of the major neurological disorders in eye leading to irreversible blindness in elderly. Increase in intraocular pressure (IOP) has been considered to be the major risk factor for the progressive loss of retinal ganglion cells (RGCs) in retina. While attenuation of IOP has been a major pharmaceutical target, reduction of IOP cannot prevent progressive loss of RGCs. In this regard, urgent need for alternative treatment has to be investigated. Anti-aging medicinal herb Lycium barbarum L. has been used for centuries in Eastern World to protect the eyes and maintain good health. Using an ocular hypertension (OH) model in rat by laser photocoagulation of episcleral and limbal veins, we attempted to investigate whether L. barbarum can promote RGCs survival against elevated IOP. Oral administration of L. barbarum in Sprague-Dawley rats (250-280 g) significantly reduced the loss of RGCs, although elevated IOP was not significantly altered. Rats fed with the 1 mg/kg extract could nearly totally escape from pressure-induced loss of RGCs. In conclusion, this is the first in vivo report showing the therapeutic function of L. barbarum against neurodegeneration in the retina of rat OH model. The results demonstrate that this extract may be a potential candidate for the development of neuroprotective drug against the loss of RGCs in glaucoma.

Antagonizing Beta-amyloid Peptide Neurotoxicity of the Anti-aging Fungus Ganoderma Lucidum

Brain Research. Jan, 2008  |  Pubmed ID: 18083148

Ganoderma lucidum (Leyss. ex Fr.) Karst. (Lingzhi) is a medicinal fungus used clinically in many Asian countries to promote health and longevity. Synaptic degeneration is another key mode of neurodegeneration in Alzheimer's disease (AD). Recent studies have shown the loss of synaptic density proteins in each individual neuron during the progression of AD. It was recently reported that beta-amyloid (Abeta) could cause synaptic dysfunction and contribute to AD pathology. In this study, we reported that aqueous extract of G. lucidum significantly attenuated Abeta-induced synaptotoxicity by preserving the synaptic density protein, synaptophysin. In addition, G. lucidum aqueous extract antagonized Abeta-triggered DEVD cleavage activities in a dose-dependent manner. Further studies elucidated that phosphorylation of c-Jun N-terminal kinase, c-Jun, and p38 MAP kinase was attenuated by G. lucidum in Abeta-stressed neurons. Taken together, the results prove a hypothesis that anti-aging G. lucidum can prevent harmful effects of the exterminating toxin Abeta in AD.

Molecular Cloning and Characterization of the Zebrafish (Danio Rerio) Telomerase Catalytic Subunit (telomerase Reverse Transcriptase, TERT)

Journal of Molecular Neuroscience : MN. 2008  |  Pubmed ID: 18157659

Telomerase is an enzyme composed of a catalytic subunit (TERT) and RNA template (TR), which specifically elongates telomeres and prevents cellular senescence. Although telomerase cannot be detected in most human somatic tissues, including the nervous system, it can be detected in teleost tissues. To facilitate the investigation of telomerase function in the teleost visual system, the coding sequence of zebrafish TERT is revealed and cloned. Immunoblot, immunohistochemistry, reverse transcription polymerase chain reaction (RT-PCR), and telomeric repeats amplification protocol (TRAP) assay are used to assess the expression of telomerase at mRNA, protein, and functional levels in zebrafish retina. Based on the amino acid sequence of mouse TERT, a full-length telomerase reverse transcriptase cDNA of zebrafish has been isolated and cloned. The deduced protein sequence contains 1,091 amino acid residues and a predicted molecular mass of 126 kDa. Multiple alignment shows that the protein sequence contains the conserved motifs and residues found in TERT of other species. RT-PCR and TRAP assay has detected TERT mRNA expression and telomerase activity, respectively, in all tissues examined, including the retina and the brain. The presence of telomerase activity indicates that a fully functional form of telomerase can be found in the retina. Immunohistochemistry reveals that most neurons in zebrafish retina express TERT in the cell nucleus. The presence of telomerase in different tissues may be associated with the indeterminate growth of teleost. However, teleost retinal neurons are post-mitotic and do not further divide under normal situation. The expression of telomerase activity and TERT in retina implies that telomerase has functions other than the elongation of telomere. These findings could provide new insights on telomerase function in the nervous system.

Evaluation of the Retina and Optic Nerve in a Rat Model of Chronic Glaucoma Using in Vivo Manganese-enhanced Magnetic Resonance Imaging

NeuroImage. Apr, 2008  |  Pubmed ID: 18272401

Glaucoma is a neurodegenerative disease of the visual system. While elevated intraocular pressure is considered to be a major risk factor, the primary cause and pathogenesis of the disease are still unclear. This study aims to employ in vivo manganese-enhanced magnetic resonance imaging (MEMRI) to evaluate dynamically the Mn(2+) enhancements in the visual components following an induction of ocular hypertension in a rat model of chronic glaucoma. The episcleral and limbal veins were photocoagulated unilaterally in the right eye using an argon laser to maintain a consistent elevation of intraocular pressure by about 1.6 times above the normal level. Two and six weeks after glaucoma induction, MnCl(2) solution (50 mM, 3 microL) was injected intravitreally into both eyes, and MEMRI was performed 2 to 5 h after injection. Results showed a delayed increase in T1-weighted signal intensity in the glaucomatous optic nerve at 6 weeks but not 2 weeks after glaucoma induction. In addition, there was an accumulation of Mn(2+) ions in the vitreous humour of the glaucomatous eye, with a high concentration of Mn(2+) ions at the optic nerve head and the retina. These MEMRI findings may help understand the disease mechanisms, monitor the effect of drug interventions in glaucoma models and complement the conventional techniques in examining the glaucomatous visual components.

Blocking LINGO-1 Function Promotes Retinal Ganglion Cell Survival Following Ocular Hypertension and Optic Nerve Transection

Investigative Ophthalmology & Visual Science. Mar, 2008  |  Pubmed ID: 18326721

LINGO-1 is a functional member of the Nogo66 receptor (NgR1)/p75 and NgR1/TROY signaling complexes that prevent axonal regeneration through RhoA in the central nervous system. LINGO-1 also promotes cell death after neuronal injury and spinal cord injury. The authors sought to examine whether blocking LINGO-1 function with LINGO-1 antagonists promotes retinal ganglion cell (RGC) survival after ocular hypertension and optic nerve transection.

Surgical Anatomy of the Chinese Orbit

Ophthalmic Plastic and Reconstructive Surgery. Mar-Apr, 2008  |  Pubmed ID: 18356720

To describe the metric measurements and normal anatomic variants in Chinese bony orbits.

Enhanced Survival of Melanopsin-expressing Retinal Ganglion Cells After Injury is Associated with the PI3 K/Akt Pathway

Cellular and Molecular Neurobiology. Dec, 2008  |  Pubmed ID: 18512147

In the present study, we studied the factors that contribute to the injury-resistant property of melanopsin-expressing retinal ganglion cells (mRGCs). Since phosphatidylinositol-3 kinase (PI3 K)/Akt signaling pathway is one of the well-known pathways for neuronal cell survival, we investigated the survival of mRGCs by applying the PI3 K/Akt specific inhibitors after injury. Two injury models, unilateral optic nerve transection and ocular hypertension, were adopted using Sprague-Dawley rats. Inhibitors of PI3 K/Akt were injected intravitreally following injuries to inhibit the PI3 K/Akt signaling pathway. Retinas were dissected after designated survival time, immunohistochemistry was carried out to visualize the mRGCs using melanopsin antibody and the number of mRGCs was counted. Co-expression of melanopsin and phospho-Akt (pAkt) was also examined. Compared to the survival of non-melanopsin-expressing RGCs, mRGCs showed a marked resistance to injury and co-expressed pAkt. Application of PI3 K/Akt inhibitors decreased the survival of mRGCs after injury. Our previous study has shown that mRGC are less susceptible to injury following the induction of ocular hypertension. In this study, we report that mRGCs were injury-resistant to a more severe type of injury, the optic nerve transection. More importantly, the PI3 K/Akt pathway was found to play a role in maintaining the survival of mRGCs after injury.

GD-DTPA Enhanced MRI of Ocular Transport in a Rat Model of Chronic Glaucoma

Experimental Eye Research. Oct, 2008  |  Pubmed ID: 18639546

Glaucoma is a neurodegenerative disease of the visual system characterized by the elevation of intraocular pressure. While this elevated pressure is related to an increased resistance to the outflow of aqueous humor from the eye, their impacts to the etiology and pathogenesis of the disease are not fully understood. This study aims to employ in vivo Gd-DTPA enhanced magnetic resonance imaging to evaluate the ocular transport following an induction of ocular hypertension in a rat model of chronic glaucoma. An experimental ocular hypertension model was induced in adult rats using an argon laser to photocoagulate the episcleral and limbal veins on the surface of the eyeball. The enhancements of the MRI signal intensity in the anterior chamber and vitreous body were measured as a function of time following systemic administration of Gd-DTPA solution at 3 mmol/kg. Results showed a progressive T1-weighted signal increase in the vitreous body of the glaucomatous eye but not the control eye. This increase occurred earlier in the anterior vitreous body than the preretinal vitreous. Further, there was an earlier Gd-DTPA transport into the anterior chamber in the majority of glaucomatous eyes. Our findings revealed the leakage of Gd-DTPA at the aqueous-vitreous interface, which was likely resulted from increased permeability of blood-aqueous or aqueous-vitreous barrier. These may explain the sources of changing biochemical compositions in the glaucomatous chamber components, which may implicate the cascades of neurodegenerative processes in the retina and the optic nerve.

Use of Anti-aging Herbal Medicine, Lycium Barbarum, Against Aging-associated Diseases. What Do We Know So Far?

Cellular and Molecular Neurobiology. Aug, 2008  |  Pubmed ID: 17710531

Lycium barbarum (Gouqizi, Fructus Lycii, Wolfberry) is well known for nourishing the liver, and in turn, improving the eyesight. However, many people have forgotten its anti-aging properties. Valuable components of L. barbarum are not limited to its colored components containing zeaxanthin and carotene, but include the polysaccharides and small molecules such as betaine, cerebroside, beta-sitosterol, p-coumaric, and various vitamins. Despite the fact that L. barbarum has been used for centuries, its beneficial effects to our bodies have not been comprehensively studied with modern technology to unravel its therapeutic effects at the biochemical level. Recently, our laboratory has demonstrated its neuroprotective effects to counter neuronal loss in neurodegenerative diseases. Polysaccharides extracted from L. barbarum can protect neurons against beta-amyloid peptide toxicity in neuronal cell cultures, and retinal ganglion cells in an experimental model of glaucoma. We have even isolated the active component of polysaccharide which can attenuate stress kinases and pro-apoptotic signaling pathways. We have accumulated scientific evidence for its anti-aging effects that should be highlighted for modern preventive medicine. This review is to provide background information and a new direction of study for the anti-aging properties of L. barbarum. We hope that new findings for L. barbarum will pave a new avenue for the use of Chinese medicine in modern evidence-based medicine.

A Neuroprotective Herbal Mixture Inhibits Caspase-3-independent Apoptosis in Retinal Ganglion Cells

Cellular and Molecular Neurobiology. Jan, 2008  |  Pubmed ID: 17710535

It was previously demonstrated that Menta-FX, a mixture of Panax quinquefolius L. (PQE), Ginkgo biloba (GBE), and Hypericum perforatum extracts (HPE), enhances retinal ganglion cell survival after axotomy. However, the mechanisms of neuroprotection remain unknown. The aim of this study is to elucidate the neuroprotective mechanisms of Menta-FX. Since PQE, GBE and HPE have all been observed to display anti-oxidative property, the involvement of anti-oxidation in Menta-FX's neuroprotective effect was investigated. Menta-FX lowered nitric oxide (NO) content in axotomized retinas without affecting nitric oxide synthase activity, suggesting that Menta-FX possibly exhibited a NO scavenging property. In addition, the effect of Menta-FX on the frequency of axotomy-induced nuclear fragmentation and caspase-3 activation was investigated. Menta-FX treatment significantly reduced nuclear fragmentation in axotomized retinas. Surprisingly, Menta-FX had no effect on caspase-3 activation, but selectively lowered caspase-3-independent nuclear fragmentation in axotomized retinal ganglion cells. In addition, inhibition of PI3K activity by intravitreal injection of wortmannin, a phosphoinositide-3 kinase (PI3K) inhibitor, completely abolished the neuroprotective effect of Menta-FX, indicating that Menta-FX's neuroprotective effect was PI3K-dependent. Data here suggest that Menta-FX displayed a PI3K-dependent, selective inhibition on a caspase-3-independent apoptotic pathway in axotomized RGCs, thus, highlighting the potential use of herbal remedies as neuroprotective agents for other neurodegenerative diseases.

Up-regulated Endogenous Erythropoietin/erythropoietin Receptor System and Exogenous Erythropoietin Rescue Retinal Ganglion Cells After Chronic Ocular Hypertension

Cellular and Molecular Neurobiology. Feb, 2008  |  Pubmed ID: 17554621

Recent studies have showed that erythropoietin (EPO) is a neuroprotectant for central nerve system neurons in addition to being a hematopoietic cytokine in response to hypoxia. In this study, we investigate the role of the EPO/EPO receptor (EPOR) system in the rat retina after ocular hypertension injury that mimics glaucoma.

Dynamic Contrast-enhanced MRI of Ocular Biotransport in Normal and Hypertensive Eyes

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2008  |  Pubmed ID: 19162786

This study aims to employ in vivo dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to evaluate the ocular transport following an induction of ocular hypertension in a rat model of chronic glaucoma. Upon systemic administration of Gd-DTPA solution, T1-weighted signal increase was observed in the vitreous body of the glaucomatous eye but not the control eye. This increase occurred earlier in the anterior vitreous body than the preretinal vitreous. Further, there was an earlier Gd-DTPA transport into the anterior chamber in the majority of glaucomatous eyes. Our DCE-MRI findings revealed the leakage of Gd-DTPA at the aqueous-vitreous interface, which was likely resulted from increased permeability of blood-aqueous or aqueous-vitreous barrier. These may explain the sources of changing biochemical compositions in the chamber components, which may implicate the neurodegenerative processes in the glaucomatous visual components.

Synaptic Degeneration of Retinal Ganglion Cells in a Rat Ocular Hypertension Glaucoma Model

Cellular and Molecular Neurobiology. Jun, 2009  |  Pubmed ID: 19172389

Glaucoma is a common neurodegenerative disease that affects retinal ganglion cells (RGCs) and their axons. Little is known of the synaptic degeneration involved in the pathophysiology of glaucoma. Here we used an experimental ocular hypertension model in rats to investigate this issue.

Intracerebroventricular Infusion of Cytosine-arabinoside Causes Prepulse Inhibition Disruption

Neuroreport. Mar, 2009  |  Pubmed ID: 19218868

Adult neurogenesis in hippocampus is associated with behaviors such as learning. Hippocampus is involved in the regulation of prepulse inhibition (PPI), but the relationship between neurogenesis and PPI is unexplored. We conducted four experiments to determine the role of neural progenitor cell proliferation in PPI. Intracerebroventricular infusion of cytostatic cytosine arabinoside caused PPI disruption but repeated exposure to PPI sessions prevented the PPI disruption. Corticosterone treatment, which decreases hippocampal cell proliferation, caused PPI disruption, whereas antidepressant and exercise, which increased cell proliferation, did not affect PPI. These results suggest that cell proliferation is involved in the first encounter with PPI test while its importance may decrease upon repeated exposures to the tests.

Post Pressure Response of Skin Blood Flowmotions in Anesthetized Rats with Spinal Cord Injury

Microvascular Research. Jun, 2009  |  Pubmed ID: 19328816

Pressure ulcer is a common complication developed in persons with spinal cord injury (SCI) when prolonged unrelieved pressure was applied to the body/skin and underlying tissues. The objective of this study is to assess the hyperemic response of the skin blood flowmotions in anesthetized rats with spinal cord injury subjected to prolonged pressure using spectral analysis based on wavelets transform of the periodic oscillations of the cutaneous laser Doppler flowmetry (LDF) signal. A total of twenty-eight Sprague-Dawley rats were used in this study, of which 14 were normal rats and the other 14 were spinal cord injured rats with transection of the T1 spinal nerves. External pressure of 13.3 kPa (100 mmHg) was applied to the trochanter area of rats via a specifically designed indentors. The loading duration was 6 h. LDF measurement was monitored for 20 min prior to and after the prescribed compression period. Five frequency intervals were identified (0.01-0.05 Hz, 0.05-0.15 Hz, 0.15-0.4 Hz, 0.4-2 Hz and 2-5 Hz) corresponding to endothelial related metabolic, neurogenic, myogenic, respiratory and cardiac origins. The absolute amplitude of oscillations of each particular frequency interval and the normalized amplitude were calculated for quantitative assessments. Comparisons of hyperemic response were performed between SCI rats and normal ones. The results showed that the normalized amplitude in the frequency interval II (0.05-0.15 Hz) was significantly lower on SCI rats than that in normal ones (p<0.01). Also, decreased reactive hyperemic response was observed in rats suffered from spinal cord injury.

Low Molecular Weight Abeta Induces Collapse of Endoplasmic Reticulum

Molecular and Cellular Neurosciences. May, 2009  |  Pubmed ID: 19386229

The endoplasmic reticulum (ER) is a dynamic multifunction organelle that is responsible for Ca(2+) homeostasis, protein folding, post-translational modification, protein degradation, and transportation of nascent proteins. Disruption of ER architecture might affect the normal physiology of the cell. In yeast, expansion of the ER is observed under unfolded protein response (UPR) and subsequently induces autophagy initiated from the ER. Here, we found that soluble low molecular weight of Abeta disrupted the anchoring between ER and microtubules (MT) and induced collapse of ER. In addition, it decreased the stability of MT. Subsequently, low molecular weight Abeta triggered autophagy and enhanced lysosomal degradation, as shown by electron microscopy and live-cell imaging. Dysfunction of ER can be further proved in postmortem AD brain and transgenic mice bearing APP Swedish mutation by immunohistochemical analysis of calreticulin. Treatment with Taxol, a MT-stabilizing agent, could partially inhibit collapse of the ER and induction of autophagy. The results show that Abeta-induced disruption of MT can affect the architecture of the ER. Collapse/aggregation of the ER may play an important role in Abeta peptide-triggered neurodegenerative processes.

The Selective Vulnerability of Retinal Ganglion Cells in Rat Chronic Ocular Hypertension Model at Early Phase

Cellular and Molecular Neurobiology. Dec, 2009  |  Pubmed ID: 19396539

Glutamate neurotoxicity has been postulated to play a prominent role in glaucoma. In this study the possible roles of two subunits of glutamate receptors during the early phase of retinal ganglion cell (RGC) loss in a rat chronic ocular hypertension (COH) model were investigated. COH was induced by applying argon laser to the episcleral and limbal veins of the right eye of rats, the observation times were at 4, 14 and 28 days after the first laser. RGCs were retrogradely labeled by putting Fluoro-Gold (FG) on the surface of both side superior colliculus. Immunohistochemical staining using specific antibodies against N-methyl-D-aspartate receptor 1 (NR1) or glutamate receptor 2/3 (GluR2/3) was performed on the retinal sections of normal and COH eyes. Fluorescent images were captured using confocal laser scanning microscope and the number of NR1 and GluR2/3 labeled cells were counted and cell size was measured using Stereo Investigator. During the observation period, the numbers of NR1 and GluR2/3 positive RGCs in the RGC layer were reduced parallel to the loss of RGC. The dramatic loss of GluR2/3 immunoreactive neurons occurred starting immediately after the first laser to 4 days while the dramatic loss of NR1 immunoreactive neurons occurred from 14 to 28 days after the first laser. Size difference was detected in NR1 immunoreactive RGCs, large ones were more sensitive to the high ocular pressure. These results suggest that both NR1 and GluR2/3 are involved in the mediation of RGC death in the early stage of COH.

Polysaccharides from Wolfberry Antagonizes Glutamate Excitotoxicity in Rat Cortical Neurons

Cellular and Molecular Neurobiology. Dec, 2009  |  Pubmed ID: 19499323

Glutamate excitotoxicity is involved in many neurodegenerative diseases including Alzheimer's disease (AD). Attenuation of glutamate toxicity is one of the therapeutic strategies for AD. Wolfberry (Lycium barbarum) is a common ingredient in oriental cuisines. A number of studies suggest that wolfberry has anti-aging properties. In recent years, there is a trend of using dried Wolfberry as food supplement and health product in UK and North America. Previously, we have demonstrated that a fraction of polysaccharide from Wolfberry (LBA) provided remarkable neuroprotective effects against beta-amyloid peptide-induced cytotoxicity in primary cultures of rat cortical neurons. To investigate whether LBA can protect neurons from other pathological factors such as glutamate found in Alzheimer brain, we examined whether it can prevent neurotoxicity elicited by glutamate in primary cultured neurons. The glutamate-induced cell death as detected by lactate dehydrogenase assay and caspase-3-like activity assay was significantly reduced by LBA at concentrations ranging from 10 to 500 microg/ml. Protective effects of LBA were comparable to memantine, a non-competitive NMDA receptor antagonist. LBA provided neuroprotection even 1 h after exposure to glutamate. In addition to glutamate, LBA attenuated N-methyl-D-aspartate (NMDA)-induced neuronal damage. To further explore whether LBA might function as antioxidant, we used hydrogen peroxide (H(2)O(2)) as oxidative stress inducer in this study. LBA could not attenuate the toxicity of H(2)O(2). Furthermore, LBA did not attenuate glutamate-induced oxidation by using NBT assay. Western blot analysis indicated that glutamate-induced phosphorylation of c-jun N-terminal kinase (JNK) was reduced by treatment with LBA. Taken together, LBA exerted significant neuroprotective effects on cultured cortical neurons exposed to glutamate.

Modulation of Microglia by Wolfberry on the Survival of Retinal Ganglion Cells in a Rat Ocular Hypertension Model

Journal of Ocular Biology, Diseases, and Informatics. Jun, 2009  |  Pubmed ID: 19672466

The active component of Wolfberry (Lycium barbarum), lycium barbarum polysaccharides (LBP), has been shown to be neuroprotective to retinal ganglion cells (RGCs) against ocular hypertension (OH). Aiming to study whether this neuroprotection is mediated via modulating immune cells in the retina, we used multiphoton confocal microscopy to investigate morphological changes of microglia in whole-mounted retinas. Retinas under OH displayed slightly activated microglia. One to 100 mg/kg LBP exerted the best neuroprotection and elicited moderately activated microglia in the inner retina with ramified appearance but thicker and focally enlarged processes. Intravitreous injection of lipopolysaccharide decreased the survival of RGCs at 4 weeks, and the activated microglia exhibited amoeboid appearance as fully activated phenotype. When activation of microglia was attenuated by intravitreous injection of macrophage/microglia inhibitory factor, protective effect of 10 mg/kg LBP was attenuated. The results implicated that neuroprotective effects of LBP were partly due to modulating the activation of microglia.

Erratum: Modulation of Microglia by Wolfberry on the Survival of Retinal Ganglion Cells in a Rat Ocular Hypertension Model

Journal of Ocular Biology, Diseases, and Informatics. Sep, 2009  |  Pubmed ID: 20046845

The active component of Wolfberry (Lycium barbarum), lycium barbarum polysaccharides (LBP), has been shown to be neuroprotective to retinal ganglion cells (RGCs) against ocular hypertension (OH). Aiming to study whether this neuroprotection is mediated via modulating immune cells in the retina, we used multiphoton confocal microscopy to investigate morphological changes of microglia in whole-mounted retinas. Retinas under OH displayed slightly activated microglia. One to 100 mg/kg LBP exerted the best neuroprotection and elicited moderately activated microglia in the inner retina with ramified appearance but thicker and focally enlarged processes. Intravitreous injection of bacterial endotoxin lipopolysaccharide (LPS) decreased the survival of RGCs at 4 weeks, and the activated microglia exhibited amoeboid appearance as fully activated phenotype. When activation of microglia was attenuated by intravitreous injection of macrophage/microglia inhibitory factor, protective effect of 10 mg/kg LBP was attenuated. The results implicated that neuroprotective effects of LBP were partly due to modulating the activation of microglia.[This corrects the article on p. in vol. .].

GAP-43 Expression Correlates with Spinal Motoneuron Regeneration Following Root Avulsion

Journal of Brachial Plexus and Peripheral Nerve Injury. 2009  |  Pubmed ID: 19852861

The growth-associated protein GAP-43 plays a crucial role in axonal regeneration in injured neurons.

Modulation of Neuroimmune Responses on Glia in the Central Nervous System: Implication in Therapeutic Intervention Against Neuroinflammation

Cellular & Molecular Immunology. Oct, 2009  |  Pubmed ID: 19887044

It has long been known that the brain is an immunologically privileged site in normal conditions. Although the cascade of immune responses can occur as long as there is a neuronal injury or a potent immune stimulation, how the brain keeps glial cells in a quiescent state is still unclear. Increasing efforts have been made by several laboratories to elucidate how repression of immune responses is achieved in the neuronal environment. The suppression factors include neurotransmitters, neurohormones, neurotrophic factors, anti-inflammatory factors, and cell-cell contact via adhesion molecules or CD200 receptor. This review discusses how these factors affect the cascade of cerebral immune responses because no single factor listed above can fully account for the immune suppression. While several factors contribute to the suppression of immune responses, activation of glial cells and their production of pro-inflammatory factors do occur as long as there is a neuronal injury, suggesting that some neuronal components facilitate immune responses. This review also discusses which signals initiate or augment cerebral immune responses so that stimulatory signals override the suppressive signals. Increasing lines of evidence have demonstrated that immune responses in the brain are not always detrimental to neurons. Attempt to simply clear off inflammatory factors in the CNS may not be appropriate for neurons in neurological disorders. Appropriate control of immune cells in the CNS may be beneficial to neurons or even neuroregeneration. Therefore, understanding the mechanisms underlying immune suppression may help us to reshape pharmacological interventions against inflammation in many neurological disorders.

Effect of Lutein on Retinal Neurons and Oxidative Stress in a Model of Acute Retinal Ischemia/reperfusion

Investigative Ophthalmology & Visual Science. Feb, 2009  |  Pubmed ID: 18936152

Retinal ischemia/reperfusion (I/R) occurs in many ocular diseases and leads to neuronal death. Lutein, a potent antioxidant, is used to prevent severe visual loss in patients with early age-related macular degeneration (AMD), but its effect on I/R insult is unclear. The objective of the present study is to investigate the neuroprotective effect of lutein on retinal neurons after acute I/R injury.

Proton Magnetic Resonance Spectroscopy Revealed Choline Reduction in the Visual Cortex in an Experimental Model of Chronic Glaucoma

Experimental Eye Research. Jan, 2009  |  Pubmed ID: 18992243

Glaucoma is a neurodegenerative disease of the visual system. While elevated intraocular pressure is considered to be a major risk factor, the primary cause and pathogenesis of this disease are still unclear. This study aims to employ in vivo proton magnetic resonance spectroscopy ((1)H MRS) to evaluate the metabolic changes in the visual cortex in a rat model of chronic glaucoma. Five Sprague-Dawley female rats were prepared to induce ocular hypertension unilaterally in the right eye by photocoagulating the episcleral and limbal veins using an argon laser. Single voxel (1)H MRS was performed on each side of the visual cortex 6 weeks after laser treatment. Relative to the creatine level, the choline level was found to be significantly lower in the left glaucomatous visual cortex than the right control visual cortex in all animals. In addition, a marginally significant increase in glutamate level was observed in the glaucomatous visual cortex. No apparent difference was observed between contralateral sides of the visual cortex in T1-weighted or T2-weighted imaging. The results of this study showed that glaucoma is accompanied with alterations in the metabolism of choline-containing compounds in the visual cortex contralateral to the glaucomatous rat eye. These potentially associated the pathophysiological mechanisms of glaucoma with the dysfunction of the cholinergic system in the visual pathway. (1)H MRS is a potential tool for studying the metabolic changes in glaucoma in vivo in normally appearing brain structures, and may possess direct clinical applications for humans. Measurement of the Cho:Cr reduction in the visual cortex may be a noninvasive biomarker for this disease.

Effects of All-trans-retinoic Acid on Human SH-SY5Y Neuroblastoma As in Vitro Model in Neurotoxicity Research

Neurotoxicology. Jan, 2009  |  Pubmed ID: 19056420

Human neuroblastoma SH-SY5Y is a dopaminergic neuronal cell line which has been used as an in vitro model for neurotoxicity experiments. Although the neuroblastoma is usually differentiated by all-trans-retinoic acid (RA), both RA-differentiated and undifferentiated SH-SY5Y cells have been used in neuroscience research. However, the changes in neuronal properties triggered by RA as well as the subsequent responsiveness to neurotoxins have not been comprehensively studied. Therefore, we aim to re-evaluate the differentiation property of RA on this cell line. We hypothesize that modulation of signaling pathways and neuronal properties during RA-mediated differentiation in SH-SY5Y cells can affect their susceptibility to neurotoxins. The differentiation property of RA was confirmed by showing an extensive outgrowth of neurites, increased expressions of neuronal nuclei, neuron specific enolase, synaptophysin and synaptic associated protein-97, and decreased expression of inhibitor of differentiation-1. While undifferentiated SH-SY5Y cells were susceptible to 6-OHDA and MPP+, RA-differentiation conferred SH-SY5Y cells higher tolerance, potentially by up-regulating survival signaling, including Akt pathway as inhibition of Akt removed RA-induced neuroprotection against 6-OHDA. As a result, the real toxicity cannot be revealed in RA-differentiated cells. Therefore, undifferentiated SH-SY5Y is more appropriate for studying neurotoxicity or neuroprotection in experimental Parkinson's disease research.

Modulation of Morphological Changes of Microglia and Neuroprotection by Monocyte Chemoattractant Protein-1 in Experimental Glaucoma

Cellular & Molecular Immunology. Jan, 2010  |  Pubmed ID: 20081877

Monocyte chemoattractant protein-1 (MCP-1)/CCL2 is a C-C chemokine involved in the activation and recruitment of monocytic cells to injury sites. MCP-1/CCL2 can induce either neuroprotection or neurodestruction in vitro, depending on the experimental model. We aim to use MCP-1/CCL2 as an experimental tool to investigate the morphological changes of microglia when loss of healthy retinal ganglion cells (RGCs) is exacerbated or attenuated in an experimental glaucoma model. While a high concentration (1000 ng) of MCP-1/CCL2 and lipopolysaccharide (LPS)-exacerbated RGC loss, 100 ng MCP-1/CCL2 provided neuroprotection towards RGC. Neuroprotective MCP-1/CCL2 (100 ng) also upregulated insulin-like growth factor-1 (IGF-1) immunoreactivity in the RGCs. The neuroprotective effect of MCP-1/CCL2 was not due to the massive infiltration of microglia/macrophages. Taken together, this is the first report showing that an appropriate amount of MCP-1/CCL2 can protect RGCs in experimental glaucoma.

Induction of C-Jun Phosphorylation in Spinal Motoneurons in Neonatal and Adult Rats Following Axonal Injury

Brain Research. Mar, 2010  |  Pubmed ID: 20096669

This study aims to address if phosphorylation of the transcription factor c-Jun is associated with lesion-induced death of spinal motoneurons, and if this cellular response is modulated by glial-cell-line-derived neurotrophic factor (GDNF). We found that after both distal axotomy and root avulsion, spinal motoneurons in neonatal rats expressed phosphorylated c-Jun (p-c-Jun) and almost all injured motoneurons in these animals died. Similarly, root avulsion in adult rats also induced p-c-Jun expression that preceded the loss of motoneurons. In contrast, neither motoneuron death nor p-c-Jun induction was found after distal axotomy of spinal nerves in adult rats. Application of GDNF after distal axotomy in the neonatal model prevented motoneuron death but did not alter the expression of p-c-Jun in the surviving motoneurons. We conclude that c-Jun phosphorylation correlates with the cellular events leading to motoneuron death and that its expression cannot be modulated by GDNF. We further showed that expression of p-c-Jun was not correlated with the expression of growth-associated protein-43 (GAP-43), whose expression was closely correlated both temporally and spatially with periods of axonal outgrowth, suggesting that p-c-Jun may not be related with axonal regeneration of injured motoneurons.

Dietary Restriction and Brain Health

Neuroscience Bulletin. Feb, 2010  |  Pubmed ID: 20101273

The benefits of dietary restriction (DR) on health and aging prevention have been well recognized. Recent studies suggest that DR may enhance brain functions including learning and memory, synaptic plasticity, and neurogenesis, all of which are associated with brain health. Under the stress stimulated by DR, a favorable environment is established for facilitating neuronal plasticity, enhancing cognitive function, stimulating neurogenesis and regulating inflammatory response. DR-induced expressions of factors such as heat shock proteins (HSPs), neurotrophic factors, and Sirtuin1 (SIRT1) are responsible for the effect of DR on the brain. Due to the difficulty in practising long-term DR in human, the potential mimics of DR are also discussed.

Generation of Human Induced Pluripotent Stem Cells from Umbilical Cord Matrix and Amniotic Membrane Mesenchymal Cells

The Journal of Biological Chemistry. Apr, 2010  |  Pubmed ID: 20139068

The umbilical cord and placenta are extra-embryonic tissues of particular interest for regenerative medicine. They share an early developmental origin and are a source of vast amounts of cells with multilineage differentiation potential that are poorly immunogenic and without controversy. Moreover, these cells are likely exempt from incorporated mutations when compared with juvenile or adult donor cells such as skin fibroblasts or keratinocytes. Here we report the efficient generation of induced pluripotent stem cells (iPSCs) from mesenchymal cells of the umbilical cord matrix (up to 0.4% of the cells became reprogrammed) and the placental amniotic membrane (up to 0.1%) using exogenous factors and a chemical mixture. iPSCs from these 2 tissues homogeneously showed human embryonic stem cell (hESC)-like characteristics including morphology, positive staining for alkaline phosphatase, normal karyotype, and expression of hESC-like markers including Nanog, Rex1, Oct4, TRA-1-60, TRA-1-80, SSEA-3, and SSEA-4. Selected clones also formed embryonic bodies and teratomas containing derivatives of the 3 germ layers, and could as well be readily differentiated into functional motor neurons. Among other things, our cell lines may prove useful for comparisons between iPSCs derived from multiple tissues regarding the extent of the epigenetic reprogramming, differentiation ability, stability of the resulting lineages, and the risk of associated abnormalities.

Neuroprotective Effects of Polysaccharides from Wolfberry, the Fruits of Lycium Barbarum, Against Homocysteine-induced Toxicity in Rat Cortical Neurons

Journal of Alzheimer's Disease : JAD. 2010  |  Pubmed ID: 20157238

Previous clinical and epidemiological studies have suggested that elevated plasma homocysteine (Hcy) levels increased the risk of Alzheime's disease (AD). Although the underlying mechanisms of its toxicity are elusive, it has been shown that Hcy damages neurons by inducing apoptosis, DNA fragmentation, and tau hyperphosphorylation. Wolfberry (Lycium barbarum) is a fruit that is known for its eye-protective and anti-aging properties in Asian countries. Previous studies from our laboratory have demonstrated that polysaccharides derived from wolfberry (LBA) have the ability to protect neurons from amyloid-beta (Abeta) peptide neurotoxicity. We hypothesize that the neuroprotective effects of wolfberry is not limited to Abeta and can also provide protection against other AD risk factors. In this study, we aim to elucidate the neuroprotective effects of wolfberry against Hcy-induced neuronal damage. Our data showed that LBA treatment significantly attenuated Hcy-induced neuronal cell death and apoptosis in primary cortical neurons as demonstrated by LDH and caspase-3 like activity assay. LBA also significantly reduced Hcy-induced tau phosphorylation at tau-1 (Ser198/199/202), pS396 (Ser396), and pS214 (Ser214) epitopes as well as cleavage of tau. At the same time, we also found that the phosphorylation level of p-GSK3beta (Ser9/Tyr 216) remained unchanged among different treatment groups at all detected time points. LBA treatment suppressed elevation of both p-ERK and p-JNK. In summary, our data demonstrated that LBA exerted neuroprotective effects on cortical neurons exposed to Hcy. Therefore, LBA has the potential to be a diseasemodifying agent for the prevention of AD.

Up-regulation of Crystallins is Involved in the Neuroprotective Effect of Wolfberry on Survival of Retinal Ganglion Cells in Rat Ocular Hypertension Model

Journal of Cellular Biochemistry. May, 2010  |  Pubmed ID: 20336662

Wolfberry (fruit of Lycium barbarum Linn) has been known for balancing 'Yin' and 'Yang' in the body, nourishing the liver and kidney, improving visual acuity for more than 2,500 years in oriental countries. The active components in wolfberry include L. barbarum polysaccharide (LBP), zeaxanthine, betaine, cerebroside and trace amounts of zinc, iron, and copper. Each of them confers distinct beneficial effects and together they help to explain widespread use of wolfberry in the eastern world. Earlier study reported the neuroprotective effects of LBP on retinal ganglion cell (RGC) in an experimental model of glaucoma and the underlying in vivo cellular mechanisms of LBP neuroprotection deserve further exploration. In this study, we adopted proteomics, functional genomics, to evaluate pharmacological effects of LBP on the neuronal survival pathways. Among the significantly changed proteins induced by LBP feeding on ocular hypertension (OH) retinas, only proteins in crystallin family were focused in this study. The proteomic results were further confirmed using the Western blotting of the retinas and immunohistochemical staining of the retinal sections. We demonstrated that neuroprotective effect of-wolfberry extract-LBP on the survival of RGCs may be mediated via direct up-regulation of neuronal survival signal betaB2-crystallin.

LINGO-1 Negatively Regulates TrkB Phosphorylation After Ocular Hypertension

The European Journal of Neuroscience. Mar, 2010  |  Pubmed ID: 20377621

The antagonism of LINGO-1, a CNS-specific negative regulator of neuronal survival, was shown to promote short-term survival of retinal ganglion cell (RGC) in an ocular hypertension model. LINGO-1 antagonists, combined with brain-derived neurotrophic factor (BDNF), can increase the length of neuron survival through an unclear molecular mechanism. To determine the relationship between LINGO-1 and BDNF/TrkB receptor in neuronal protection, we show here that LINGO-1 forms a receptor complex with TrkB and negatively regulates its activation in the retina after ocular hypertension injury. LINGO-1 antagonist antibody 1A7 or soluble LINGO-1 (LINGO-1-Fc) treatment upregulates phospho-TrkB phosphorylation and leads to RGC survival after high intraocular pressure injury. This neuronal protective effect was blocked by anti-BDNF antibody. LINGO-1 antagonism therefore promotes RGC survival by regulating the BDNF and TrkB signaling pathway after ocular hypertension.

Roles of Paroxetine and Corticosterone on Adult Mammalian Ciliary Body Cell Proliferation

Chinese Medical Journal. May, 2010  |  Pubmed ID: 20529586

The neurogenesis in retina of adult mammals is generally abolished, and this renders the retina lack of regenerative capacity. Despite this, there is a small population of nestin-positive cells in the ciliary epithelium which retains neurogenic potential. The present study aimed at investigating the effect of two drugs, corticosterone and paroxetine, on the cell proliferation of the ciliary body.

Visual Response Properties of Y Cells in the Detached Feline Retina

Investigative Ophthalmology & Visual Science. Feb, 2010  |  Pubmed ID: 19797207

To evaluate early changes in the visual response properties of Y cells in the detached feline retina.

Anti-aging Herbal Medicine--how and Why Can They Be Used in Aging-associated Neurodegenerative Diseases?

Ageing Research Reviews. Jul, 2010  |  Pubmed ID: 19833234

Aging is a universal biological process that leads to progressive and deleterious changes in organisms. From ancient time, mankind has already interested in preventing and keeping ourselves young. Anti-aging study is certainly not a new research area. Nowadays, the meaning of anti-aging has been changed from simply prolonging lifespan to increasing health span, which emphasizes more on the quality of life. This is the concept of healthy aging and prevention of pathological aging, which is associated with diseases. Keeping our brain functions as in young age is an important task for neuroscientists to prevent aging-associated neurological disorders, such as Alzheimer's diseases (AD) and Parkinson's disease (PD). The causes of these diseases are not fully understood, but it is believed that these diseases are affected by multiple factors. Neurodegenerative diseases can be cross-linked with a number of aging-associated conditions. Based on this, a holistic approach in anti-aging research seems to be more reasonable. Herbal medicine has a long history in Asian countries. It is believed that many of the medicinal herbs have anti-aging properties. Recent studies have shown that some medicinal herbs are effective in intervention or prevention of aging-associated neurological disorders. In this review, we use wolfberry and ginseng as examples to elaborate the properties of anti-aging herbs. The characteristics of medicinal herbs, especially their applications in different disease stages (prevention and intervention) and multi-targets properties, allow them to be potential anti-aging intervention in prevention and treatment of the aging-associated neurological disorders.

In Vivo MRI Study of the Visual System in Normal, Developing and Injured Rodent Brains

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2010  |  Pubmed ID: 21097319

This paper demonstrated our recent use of contrast-enhanced MRI, diffusion tensor/kurtosis imaging, proton magnetic resonance spectroscopy, and functional MRI techniques, for in vivo and global assessments of the structure, metabolism and function of the visual system in rodent studies of ocular diseases, optic neuropathies, developmental plasticity and neonatal hypoxic-ischemic brain injury at 7T. Results suggested the significant values of high-field multiparametric MRI for uncovering the processes and mechanisms of developmental and pathophysiological changes systematically along both anterior and posterior visual pathways, and may provide early diagnoses and therapeutic strategies for promoting functional recovery upon partial vision loss.

Co-expression of GAP-43 and NNOS in Avulsed Motoneurons and Their Potential Role for Motoneuron Regeneration

Nitric Oxide : Biology and Chemistry / Official Journal of the Nitric Oxide Society. Dec, 2010  |  Pubmed ID: 20667480

Neuronal nitric oxide synthase (nNOS) is induced after axonal injury. The role of induced nNOS in injured neurons is not well established. In the present study, we investigated the co-expression of nNOS with GAP-43 in spinal motoneurons following axonal injury. The role of induced nNOS was discussed and evaluated. In normal rats, spinal motoneurons do not express nNOS or GAP-43. Following spinal root avulsion, expression of nNOS and GAP-43 were induced and colocalized in avulsed motoneurons. Reimplantation of avulsed roots resulted in a remarkable decrease of GAP-43- and nNOS-IR in the soma of the injured motoneurons. A number of GAP-43-IR regenerating motor axons were found in the reimplanted nerve. In contrast, the nNOS-IR was absent in reimplanted nerve. These results suggest that expression of GAP-43 in avulsed motoneurons is related to axonal regeneration whereas nNOS is not.

Adiponectin Protects Rat Hippocampal Neurons Against Excitotoxicity

Age (Dordrecht, Netherlands). Jun, 2011  |  Pubmed ID: 20842535

Adiponectin exerts multiple regulatory functions in the body and in the hypothalamus primarily through activation of its two receptors, adiponectin receptor1 and adiponectin receptor 2. Recent studies have shown that adiponectin receptors are widely expressed in other areas of the brain including the hippocampus. However, the functions of adiponectin in brain regions other than the hypothalamus are not clear. Here, we report that adiponectin can protect cultured hippocampal neurons against kainic acid-induced (KA) cytotoxicity. Adiponectin reduced the level of reactive oxygen species, attenuated apoptotic cell death, and also suppressed activation of caspase-3 induced by KA. Pretreatment of hippocampal primary neurons with an AMPK inhibitor, compound C, abolished adiponectin-induced neuronal protection. The AMPK activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, attenuated KA-induced caspase-3 activity. These findings suggest that the AMPK pathway is critically involved in adiponectin-induced neuroprotection and may mediate the antioxidative and anti-apoptotic properties of adiponectin.

Reproduction: a New Venue for Studying Function of Adult Neurogenesis?

Cell Transplantation. 2011  |  Pubmed ID: 20887675

Adult neurogenesis has been a focus within the past few years because it is a newly recognized form of neuroplasticity that may play significant roles in behaviors and recovery process after disease. Mammalian adult neurogenesis could be found in two brain regions: hippocampus and subventricular zone (SVZ). While it is well established that hippocampal neurogenesis participates in memory formation and anxiety, the physiological function of SVZ neurogenesis is still under intense investigation. Recent studies disclose that SVZ neurogenesis is under regulation of reproductive cues like pheromones. Reciprocally, the newborn neurons may exert their effect on reproductive and maternal behaviors. This review discusses recent understanding of the interrelationship between neurogenesis and reproduction. The studies highlighted in this review illustrate the potential importance of neurogenesis in reproductive function and will provide new insights for the significance of adult neurogenesis.

Adult Hippocampal Neurogenesis: a Possible Way How Physical Exercise Counteracts Stress

Cell Transplantation. 2011  |  Pubmed ID: 20887683

It was considered that neurogenesis only occurred during the embryonic and developmental stage. This view has greatly changed since the discovery of adult neurogenesis in two brain regions: the hippocampus and the olfactory bulb. Recently, it is suggested that altered hippocampal neurogenesis is related to pathophysiology of mood disorders and mechanism of antidepressant treatments. Accumulating knowledge about the effects of physical exercise on brain function suggests a special role of adult hippocampal neurogenesis in cognitive and mental health, even though the functional significance of adult neurogenesis is still debated. The beneficial effects of running correlating with increased adult neurogenesis may provide a hint that newborn neurons may be involved, at least in part, in the counteractive mechanism of physical exercise on stress-related disorders, like depression. The present review provides an overview of recent findings to emphasize the possible involvement of hippocampal neurogenesis in mediating the beneficial effects of physical exercise on counteracting stress.

Effect of Corticosterone and Paroxetine on Masculine Mating Behavior: Possible Involvement of Neurogenesis

The Journal of Sexual Medicine. May, 2011  |  Pubmed ID: 20955318

Corticosterone inhibits male rodent sexual behavior while the mechanism remains obscured. Recent studies have disclosed that neurogenesis in the subventricular zone (SVZ) can be increased by pheromone exposure from the opposite sex, and neurogenesis is essential for normal mating behavior of female mice. Together with the neurogenesis-inhibiting effect of corticosterone, we hypothesize that cell proliferation in the olfactory system is essential for male rodent sexual functioning.

Light Deprivation Induces Depression-like Behavior and Suppresses Neurogenesis in Diurnal Mongolian Gerbil (Meriones Unguiculatus)

Cell Transplantation. 2011  |  Pubmed ID: 21054936

Recent evidence suggests that adult neurogenesis contributes to the pathophysiology of different psychiatric disorders, including depressive disorder, anxiety disorder, and schizophrenia. Seasonal affective disorder (SAD) is a specific form of recurrent depressive disorder that can be induced by shortened light period. It is unclear yet whether neurogenesis is affected in SAD or under altered light/dark cycle. The present study aims at examining whether neurogenesis and dendritic growth of immature neurons are affected in Mongolian gerbils, a mainly diurnal rodent, under light deprivation. Animals were divided into two groups: the control (kept in 12 h light:12 h dark) and the light-deprived groups (kept in 24 h dark). Depression-like behaviors and neurogenesis were assessed after 2 weeks. Compared with the control group, light-deprived gerbils showed increased immobile time in the tail suspension test and forced swimming test, which indicates induction of depression-like behavior. Cell proliferation in both the hippocampal and subventricular zone were significantly decreased in the light-deprived group, which also showed a decreased neuronal differentiation. Dendritic maturation of immature neurons was suppressed by light deprivation, which is revealed by doublecortin staining and Sholl analysis. The results revealed that the light/dark cycle exerts impacts on neurogenesis and maturation of new neurons. Additionally, the current experiment may offer a model for exploring the relationship among daylight exposure, circadian cycles, depressive behavior, and the underlying mechanisms.

Hippocampal Neurogenesis and Dendritic Plasticity Support Running-improved Spatial Learning and Depression-like Behaviour in Stressed Rats

PloS One. 2011  |  Pubmed ID: 21935393

Exercise promotes hippocampal neurogenesis and dendritic plasticity while stress shows the opposite effects, suggesting a possible mechanism for exercise to counteract stress. Changes in hippocampal neurogenesis and dendritic modification occur simultaneously in rats with stress or exercise; however, it is unclear whether neurogenesis or dendritic remodeling has a greater impact on mediating the effect of exercise on stress since they have been separately examined. Here we examined hippocampal cell proliferation in runners treated with different doses (low: 30 mg/kg; moderate: 40 mg/kg; high: 50 mg/kg) of corticosterone (CORT) for 14 days. Water maze task and forced swim tests were applied to assess hippocampal-dependent learning and depression-like behaviour respectively the day after the treatment. Repeated CORT treatment resulted in a graded increase in depression-like behaviour and impaired spatial learning that is associated with decreased hippocampal cell proliferation and BDNF levels. Running reversed these effects in rats treated with low or moderate, but not high doses of CORT. Using 40 mg/kg CORT-treated rats, we further studied the role of neurogenesis and dendritic remodeling in mediating the effects of exercise on stress. Co-labelling with BrdU (thymidine analog) /doublecortin (immature neuronal marker) showed that running increased neuronal differentiation in vehicle- and CORT-treated rats. Running also increased dendritic length and spine density in CA3 pyramidal neurons in 40 mg/kg CORT-treated rats. Ablation of neurogenesis with Ara-c infusion diminished the effect of running on restoring spatial learning and decreasing depression-like behaviour in 40 mg/kg CORT-treated animals in spite of dendritic and spine enhancement. but not normal runners with enhanced dendritic length. The results indicate that both restored hippocampal neurogenesis and dendritic remodelling within the hippocampus are essential for running to counteract stress.

Soluble Nogo-66 Receptor Prevents Synaptic Dysfunction and Rescues Retinal Ganglion Cell Loss in Chronic Glaucoma

Investigative Ophthalmology & Visual Science. Oct, 2011  |  Pubmed ID: 21948553

Myelin inhibitory proteins inhibit axon growth and synaptic function by binding to the Nogo-66 receptor (NgR)1 in the central nervous system. Glaucoma is a progressive neuropathy characterized by loss of vision as a result of retinal ganglion cell (RGC) death. Synaptic degeneration is thought to be an early pathology of neurodegeneration in glaucoma and precedes RGC loss. The authors aimed to examine whether the NgR1 antagonist promotes synaptic recovery and RGC survival in glaucoma.

Elevated Blood Pressure Aggravates Intracerebral Hemorrhage-induced Brain Injury

Journal of Neurotrauma. Dec, 2011  |  Pubmed ID: 21988112

Elevated blood pressure (BP) is commonly seen in patients with intracerebral hemorrhage (ICH), and is independently associated with poor functional outcomes. Little is known about how elevated BP influences ICH-related brain injury. In the present study, we investigated the physiological and brain histological changes, as well as functional recovery following ICH in renovascular hypertensive rats. Renovascular hypertension (RVHT) was achieved by applying a silver clip onto the left renal artery of adult Sprague-Dawley rats. ICH was induced by an intrastriatal injection of bacterial collagenase IV about 5-6 weeks after left renal artery clipping or the sham operation. Following induction of ICH, both the normotensive and RVHT rats demonstrated an ultra-acute elevation in BP. Elevated BP increased hematoma volume, brain swelling, and apoptosis in the perihematomal areas. Brain degeneration, including local atrophy and lateral ventricle enlargement, was greater in the RVHT rats. In addition, many proliferating cells were seen over the ipsilateral striatum in the RVHT rats after ICH. The modified limb placing tests were done weekly for 3 weeks. In line with the histological damage, elevated BP worsened neurological deficits. These results suggest that ICH in the hypertensive rats mimics the clinical scenario of hypertensive ICH and may provide a platform to study the mechanisms of ICH-induced brain injury and potential therapies for ICH.

Endoplasmic Reticulum Stress Induces Tau Pathology and Forms a Vicious Cycle: Implication in Alzheimer's Disease Pathogenesis

Journal of Alzheimer's Disease : JAD. Nov, 2011  |  Pubmed ID: 22101233

Accumulation of unfolded proteins can disturb the functions of the endoplasmic reticulum (ER), leading to ER-stress or unfolded protein response (UPR). Recent data have shown that activation of UPR can be found in postmortem brains of Alzheimer's disease (AD) patients; and biological markers for activation of UPR are abundant in neurons with diffuse phosphorylated tau. Although these observations suggest a linkage between ER-stress and tau pathology, little is known of their relationship. In this study, we found that high levels of phosphorylated PKR-like ER-resident kinase (p-PERK) and phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) as markers for activation of UPR in the hippocampus of aged P301L mutant tau transgenic mice. The immunoreactivity of p-PERK was found to co-localize with that of phosphorylated tau. We then hypothesized that phosphorylation of tau could induce ER-stress and vice versa in promoting AD-like pathogenesis. By using the protein phosphatase 2A inhibitor okadaic acid (OA) as an inducer for phosphorylation of tau, we found that primary cultures of rat cortical neurons treated with OA triggered UPR as indicated by increased levels of p-PERK and p-eIF2α, splicing of mRNA for xbp-1 and elevated levels of mRNA for GADD153. On the other hand, thapsigargin as an ER-stress inducer stimulated phosphorylation of tau at Thr231, Ser262 and Ser396. Thapsigargin also induced activation of caspase-3 and cleavage of tau. These findings suggested that ER-stress and hyperphosphorylation of tau could be induced by each other to form a vicious cycle to propagate AD-like neurodegeneration.

Long-term in Vivo Imaging and Measurement of Dendritic Shrinkage of Retinal Ganglion Cells

Investigative Ophthalmology & Visual Science. Mar, 2011  |  Pubmed ID: 21245394

To monitor and measure dendritic shrinkage of retinal ganglion cells (RGCs) in a strain of transgenic mice (Thy-1 YFP) that expresses yellow fluorescent proteins in neurons under the control of a Thy-1 promoter.

Lycium Barbarum Polysaccharides Reduce Neuronal Damage, Blood-retinal Barrier Disruption and Oxidative Stress in Retinal Ischemia/reperfusion Injury

PloS One. 2011  |  Pubmed ID: 21298100

Neuronal cell death, glial cell activation, retinal swelling and oxidative injury are complications in retinal ischemia/reperfusion (I/R) injuries. Lycium barbarum polysaccharides (LBP), extracts from the wolfberries, are good for "eye health" according to Chinese medicine. The aim of our present study is to explore the use of LBP in retinal I/R injury. Retinal I/R injury was induced by surgical occlusion of the internal carotid artery. Prior to induction of ischemia, mice were treated orally with either vehicle (PBS) or LBP (1 mg/kg) once a day for 1 week. Paraffin-embedded retinal sections were prepared. Viable cells were counted; apoptosis was assessed using TUNEL assay. Expression levels of glial fibrillary acidic protein (GFAP), aquaporin-4 (AQP4), poly(ADP-ribose) (PAR) and nitrotyrosine (NT) were investigated by immunohistochemistry. The integrity of blood-retinal barrier (BRB) was examined by IgG extravasations. Apoptosis and decreased viable cell count were found in the ganglion cell layer (GCL) and the inner nuclear layer (INL) of the vehicle-treated I/R retina. Additionally, increased retinal thickness, GFAP activation, AQP4 up-regulation, IgG extravasations and PAR expression levels were observed in the vehicle-treated I/R retina. Many of these changes were diminished or abolished in the LBP-treated I/R retina. Pre-treatment with LBP for 1 week effectively protected the retina from neuronal death, apoptosis, glial cell activation, aquaporin water channel up-regulation, disruption of BRB and oxidative stress. The present study suggests that LBP may have a neuroprotective role to play in ocular diseases for which I/R is a feature.

Caveolin-1 Promote Astroglial Differentiation of Neural Stem/progenitor Cells Through Modulating Notch1/NICD and Hes1 Expressions

Biochemical and Biophysical Research Communications. Apr, 2011  |  Pubmed ID: 21414292

In the present study, we aim to elucidate the role of caveolin-1 in modulating astroglial differentiation of neural progenitor cells (NPCs) and the potential mechanisms involved. We first investigated astroglial differentiation and Notch signaling by detecting the expressions of S100β, GFAP, NICD and hairy enhancer of split 1 (Hes1) in the brains of wild-type and caveolin-1 knockout mice. Caveolin-1 knockout mice revealed remarkably less astroglial differentiation and lower levels of NICD and Hes1 expressions than wild type mice. We then studied the potential roles of caveolin-1 in modulating NICD and Hes1 expressions and astroglial differentiation in isolated cultured NPCs by using caveolin-1 peptide and caveolin-1 RNA silencing. In the differentiating NPCs, caveolin-1 peptide markedly promoted astroglial formation and up-regulated the expressions of NICD and Hes1. In contrast, the knockdown of caveolin-1 inhibited astroglial differentiation of NPCs and the expressions of NICD and Hes1. Taken together, these results provide strong evidence that caveolin-1 can promote astroglial differentiation of NPCs through modulating Notch1/NICD and Hes1 expressions.

Learning New Color Names Produces Rapid Increase in Gray Matter in the Intact Adult Human Cortex

Proceedings of the National Academy of Sciences of the United States of America. Apr, 2011  |  Pubmed ID: 21464316

The human brain has been shown to exhibit changes in the volume and density of gray matter as a result of training over periods of several weeks or longer. We show that these changes can be induced much faster by using a training method that is claimed to simulate the rapid learning of word meanings by children. Using whole-brain magnetic resonance imaging (MRI) we show that learning newly defined and named subcategories of the universal categories green and blue in a period of 2 h increases the volume of gray matter in V2/3 of the left visual cortex, a region known to mediate color vision. This pattern of findings demonstrates that the anatomical structure of the adult human brain can change very quickly, specifically during the acquisition of new, named categories. Also, prior behavioral and neuroimaging research has shown that differences between languages in the boundaries of named color categories influence the categorical perception of color, as assessed by judgments of relative similarity, by response time in alternative forced-choice tasks, and by visual search. Moreover, further behavioral studies (visual search) and brain imaging studies have suggested strongly that the categorical effect of language on color processing is left-lateralized, i.e., mediated by activity in the left cerebral hemisphere in adults (hence "lateralized Whorfian" effects). The present results appear to provide a structural basis in the brain for the behavioral and neurophysiologically observed indices of these Whorfian effects on color processing.

Drug Discovery from Chinese Medicine Against Neurodegeneration in Alzheimer's and Vascular Dementia

Chinese Medicine. 2011  |  Pubmed ID: 21513513

Alzheimer's disease and vascular dementia are two major diseases associated with dementia, which is common among the elderly. While the etiology of dementia is multi-factorial and complex, neurodegeneration may be the major cause of these two diseases. Effective drugs for treating dementia are still to be discovered. Current western pharmacological approaches against neurodegeneration in dementia develop symptom-relieving and disease-modifying drugs. Current integrative and holistic approaches of Chinese medicine to discovering drugs for neurodegeneration in dementia include (1) single molecules from the herbs, (2) standardized extracts from a single herb, and (3) herbal formula with definite composition. This article not only reviews the concept of dementia in western medicine and Chinese medicine but also evaluates the advantages and disadvantages of these approaches.

Y-like Retinal Ganglion Cells Innervate the Dorsal Raphe Nucleus in the Mongolian Gerbil (Meriones Unguiculatus)

PloS One. 2011  |  Pubmed ID: 21552551

The dorsal raphe nucleus (DRN) of the mesencephalon is a complex multi-functional and multi-transmitter nucleus involved in a wide range of behavioral and physiological processes. The DRN receives a direct input from the retina. However little is known regarding the type of retinal ganglion cell (RGC) that innervates the DRN. We examined morphological characteristics and physiological properties of these DRN projecting ganglion cells.

Neurodegeneration of the Retina in Mouse Models of Alzheimer's Disease: What Can We Learn from the Retina?

Age (Dordrecht, Netherlands). May, 2011  |  Pubmed ID: 21559868

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disease commonly found among elderly. In addition to cognitive and behavioral deficits, vision abnormalities are prevalent in AD patients. Recent studies investigating retinal changes in AD double-transgenic mice have shown altered processing of amyloid precursor protein and accumulation of β-amyloid peptides in neurons of retinal ganglion cell layer (RGCL) and inner nuclear layer (INL). Apoptotic cells were also detected in the RGCL. Thus, the pathophysiological changes of retinas in AD patients are possibly resembled by AD transgenic models. The retina is a simple model of the brain in the sense that some pathological changes and therapeutic strategies from the retina may be observed or applicable to the brain. Furthermore, it is also possible to advance our understanding of pathological mechanisms in other retinal degenerative diseases. Therefore, studying AD-related retinal degeneration is a promising way for the investigation on (1) AD pathologies and therapies that would eventually benefit the brain and (2) cellular mechanisms in other retinal degenerations such as glaucoma and age-related macular degeneration. This review will highlight the efforts on retinal degenerative research using AD transgenic mouse models.

The Expression Patterns of Nogo-A, Myelin Associated Glycoprotein and Oligodendrocyte Myelin Glycoprotein in the Retina After Ocular Hypertension: the Expression of Myelin Proteins in the Retina in Glaucoma

Neurochemical Research. Nov, 2011  |  Pubmed ID: 21643729

Nogo-A, a major myelin inhibitory protein, inhibits axon growth and synaptic function in the central nervous system. Glaucoma is a progressive neuropathy as a result of retinal ganglion cell (RGC) death. Synaptic degeneration is thought to be an early pathology of neurodegeneration in glaucoma and precedes RGC loss. Here experimental ocular hypertension model was induced in adult rats with laser coagulation of the episcleral and limbal veins. The expression of Nogo-A, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp) in the retina was investigated using immunohistochemistry and Western blotting. We found that Nogo-A was expressed in the RGCs and upregulated after the induction of ocular hypertension. OMgp was only expressed in the inner plexiform layer. There was no MAG expression in the retina. Our data provided, for the first time, the expression patterns of three myelin proteins in the adult retina and suggested an important role of Nogo-A in the RGC death and synaptic degeneration in glaucoma.

Caveolin-1 Inhibits Oligodendroglial Differentiation of Neural Stem/progenitor Cells Through Modulating β-catenin Expression

Neurochemistry International. Aug, 2011  |  Pubmed ID: 21693146

In the present study, we aim to elucidate the role of caveolin-1 (Cav-1) in modulating oligodendroglial differentiation of neural progenitor cells (NPCs) in vivo and in vitro. For in vivo experiments, we investigated oligodendroglial differentiation by detecting the expressions of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and β-catenin in the brains of wild type mice and Cav-1 knockout mice. Cav-1 knockout mice revealed more oligodendroglial differentiation, but lower levels of β-catenin expression than wild type mice. For in vitro experiments, we observed the potential roles of Cav-1 in modulating β-catenin expression and oligodendroglial differentiation in isolated cultured NPCs by manipulating Cav-1 expression with Cav-1 scaffolding domain peptide and Cav-1 RNA silencing approach. In the differentiating NPCs, Cav-1 scaffolding domain peptide markedly inhibited oligodendroglial formation, but up-regulated the expression of β-catenin. In contrast, the knockdown of Cav-1 promoted oligodendroglial differentiation of NPCs, but down-regulated the expression of β-catenin. Taken together, these results directly prove that caveolin-1 can inhibit oligodendroglial differentiation of NPCs through modulating β-catenin expression.

Soluble NgR Fusion Protein Modulates the Proliferation of Neural Progenitor Cells Via the Notch Pathway

Neurochemical Research. Dec, 2011  |  Pubmed ID: 21822922

NogoA, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein are CNS myelin molecules that bind to the neuronal Nogo-66 receptor (NgR) and inhibit axon growth. The NgR antagonist, soluble NgR1-Fc protein (sNgR-Fc), facilitates axon regeneration by neutralizing the inhibitory effects of myelin proteins in experimental models of CNS injury. Here we aim to investigate the effect of sNgR-Fc on the proliferation of neural progenitor cells (NPCs). The hippocampus cells of embryonic rats were isolated and cultured in vitro. The expression of nestin, βIII-Tubulin, GFAP and Nogo-A on these cells was observed using immunocytochemistry. In order to investigate the effect on proliferation of NPCs, sNgR-Fc, MAG-Fc chimera and Notch1 blocker were added respectively. The total cell number for the proliferated NPCs was counted. BrdU was applied and the rate of proliferating cells was examined. The level of Notch1 was analyzed using Western blotting. We identified that NogoA is expressed in NPCs. sNgR-Fc significantly enhanced the proliferation of NPCs in vitro as indicated by BrdU labeling and total cell count. This proliferation effect was abolished by the administration of MAG suggesting specificity. In addition, we demonstrate that sNgR-Fc is a potent activator for Notch1 and Notch1 antagonist reversed the effect of sNgR-Fc on NPC proliferation. Our results suggest that sNgR-Fc may modulate Nogo activity to induce NPC proliferation via the Notch pathway.

Caveolin-1 Plays a Crucial Role in Inhibiting Neuronal Differentiation of Neural Stem/progenitor Cells Via VEGF Signaling-dependent Pathway

PloS One. 2011  |  Pubmed ID: 21826216

In the present study, we aim to elucidate the roles of caveolin-1(Cav-1), a 22 kDa protein in plasma membrane invaginations, in modulating neuronal differentiation of neural progenitor cells (NPCs). In the hippocampal dentate gyrus, we found that Cav-1 knockout mice revealed remarkably higher levels of vascular endothelial growth factor (VEGF) and the more abundant formation of newborn neurons than wild type mice. We then studied the potential mechanisms of Cav-1 in modulating VEGF signaling and neuronal differentiation in isolated cultured NPCs under normoxic and hypoxic conditions. Hypoxic embryonic rat NPCs were exposed to 1% O₂ for 24 h and then switched to 21% O₂ for 1, 3, 7 and 14 days whereas normoxic NPCs were continuously cultured with 21% O₂. Compared with normoxic NPCs, hypoxic NPCs had down-regulated expression of Cav-1 and up-regulated VEGF expression and p44/42MAPK phosphorylation, and enhanced neuronal differentiation. We further studied the roles of Cav-1 in inhibiting neuronal differentiation by using Cav-1 scaffolding domain peptide and Cav-1-specific small interfering RNA. In both normoxic and hypoxic NPCs, Cav-1 peptide markedly down-regulated the expressions of VEGF and flk1, decreased the phosphorylations of p44/42MAPK, Akt and Stat3, and inhibited neuronal differentiation, whereas the knockdown of Cav-1 promoted the expression of VEGF, phosphorylations of p44/42MAPK, Akt and Stat3, and stimulated neuronal differentiation. Moreover, the enhanced phosphorylations of p44/42MAPK, Akt and Stat3, and neuronal differentiation were abolished by co-treatment of VEGF inhibitor V1. These results provide strong evidence to prove that Cav-1 can inhibit neuronal differentiation via down-regulations of VEGF, p44/42MAPK, Akt and Stat3 signaling pathways, and that VEGF signaling is a crucial target of Cav-1. The hypoxia-induced down-regulation of Cav-1 contributes to enhanced neuronal differentiation in NPCs.

Effect of Inner Retinal Dysfunction on Slow Double-stimulation Multifocal Electroretinogram

The British Journal of Ophthalmology. Nov, 2011  |  Pubmed ID: 21849350

This study investigated the retinal adaptive mechanism in inner retinal dysfunction using the slow double-stimulation multifocal electroretinogram (mfERG) paradigm.

In Vivo Retinotopic Mapping of Superior Colliculus Using Manganese-enhanced Magnetic Resonance Imaging

NeuroImage. Jan, 2011  |  Pubmed ID: 20633657

The superior colliculus (SC) is a dome-shaped subcortical laminar structure in the mammalian midbrain, whose superficial layers receive visual information from the retina in a topological order. Despite the increasing number of studies investigating retinotopic projection in visual brain development and disorders, in vivo, high-resolution 3D mapping of topographic organization in the subcortical visual nuclei has not yet been available. This study explores the capability of 3D manganese-enhanced MRI (MEMRI) at 200 μm isotropic resolution for in vivo retinotopic mapping of the rat SC upon partial transection of the intraorbital optic nerve. One day after intravitreal Mn(2+) injection into both eyes, animals with partial transection at the right superior intraorbital optic nerve in Group 1 (n=8) exhibited a significantly lower T1-weighted signal intensity in the lateral region of the left SC compared to the left medial SC and right control SC. Partial transection toward the temporal or nasal region of the right intraorbital optic nerve in Group 2 (n=7) led to T1-weighted hypointensity in the rostral or caudal region of the left SC, whereas a clear border was observed separating 2 halves of the left SC in all groups. Previous histological and electrophysiological studies showed that the retinal ganglion cell axons emanating from superior, inferior, nasal and temporal retina projected respectively to the contralateral lateral, medial, caudal and rostral SC in rodents. While this topological pattern is preserved in the intraorbital optic nerve, it was shown that partial transection of the superior intraorbital optic nerve led to primary injury predominantly in the superior but not inferior retina and optic nerve. The results of this study demonstrated the sensitivity of submillimeter-resolution MEMRI for in vivo, 3D mapping of the precise retinotopic projections in SC upon reduced anterograde axonal transport of Mn(2+) ions from localized regions of the anterior visual pathways to the subcortical midbrain nuclei. Future MEMRI studies are envisioned that measure the topographic changes in brain development, diseases, plasticity and regeneration therapies in a global and longitudinal setting.

Temporal Relationship of Autophagy and Apoptosis in Neurons Challenged by Low Molecular Weight β-amyloid Peptide

Journal of Cellular and Molecular Medicine. Feb, 2011  |  Pubmed ID: 20015199

Alzheimer's disease (AD) is an aging-related progressive neurodegenerative disorder. Previous studies suggested that various soluble Aβ species are neurotoxic and able to activate apoptosis and autophagy, the type I and type II programmed cell death, respectively. However, the sequential and functional relationships between these two cellular events remain elusive. Here we report that low molecular weight Aβ triggered cleavage of caspase 3 and poly (ADP-ribose) polymerase to cause neuronal apoptosis in rat cortical neurons. On the other hand, Aβ activated autophagy by inducing autophagic vesicle formation and autophagy related gene 12 (ATG12), and up-regulated the lysoso-mal machinery for the degradation of autophagosomes. Moreover, we demonstrated that activation of autophagy by Aβ preceded that of apoptosis, with death associated protein kinase phosphorylation as the potential molecular link. More importantly, under Aβ toxicity, neurons exhibiting high level of autophagosome formation were absent of apoptotic features, and inhibition of autophagy by 3-methylade-nine advanced neuronal apoptosis, suggesting that autophagy can protect neurons from Aβ-induced apoptosis.

Luminance-modulated Adaptation in the Global Flash MfERG: a Preliminary Study of Early Retinal Functional Changes in High-risk Glaucoma Patients

Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Für Klinische Und Experimentelle Ophthalmologie. Feb, 2012  |  Pubmed ID: 21881844

To investigate the association of the luminance-modulation global flash multifocal electroretinogram (mfERG) and other clinical assessments of vision in subsets of subjects at high risk of developing glaucomatous damage.

Lycium Barbarum Polysaccharides Protect Mice Liver from Carbon Tetrachloride-induced Oxidative Stress and Necroinflammation

Journal of Ethnopharmacology. Jan, 2012  |  Pubmed ID: 22138659

Lycium barbarum has been used as a traditional Chinese medicine to nourish liver, kidneys and the eyes.

Neuroprotection Provided by Dietary Restriction in Rats is Further Enhanced by Reducing Glucocortocoids

Neurobiology of Aging. Jan, 2012  |  Pubmed ID: 22226488

Glucocorticoids (GC)-corticosterone (CORT) in rodents and cortisol in primates-are stress-induced hormones secreted by adrenal glands that interact with the hypothalamic pituitary axis. High levels of cortisol in humans are observed in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), as well as in diabetes, post-traumatic stress syndrome, and major depression. Experimental models of diabetes in rats and mice have demonstrated that reduction of CORT reduces learning and memory deficits and attenuates loss of neuronal viability and plasticity. In contrast to the negative associations of elevated GC levels, CORT is moderately elevated in dietary restriction (DR) paradigms which are associated with many healthy anti-aging effects including neuroprotection. We demonstrate here in rats that ablating CORT by adrenalectomy (ADX) with replenishment to relatively low levels (30% below that of controls) prior to the onset of a DR regimen (ADX-DR) followed by central administration of the neurotoxin, kainic acid (KA), significantly attenuates learning deficits in a 14-unit T-maze task. The performance of the ADX-DR KA group did not differ from a control group (CON) that did not receive KA and was fed ad libitum (AL). By contrast, the sham-operated DR (SHAM-DR KA) group, SHAM-AL KA group, and ADX-AL KA group demonstrated poorer learning behavior in this task compared to the CON group. Stereological analysis revealed equivalent DR-induced neuroprotection in the SH-DR KA and ADX-DR KA groups, as measured by cell loss in the CA2/CA3 region of the hippocampus, while substantial cell loss was observed in SH-AL and ADX-AL rats. A separate set of experiments was conducted with similar dietary and surgical treatment conditions but without KA administration to examine markers of neurotrophic activity, brain-derived neurotrophic factor (BDNF), transcriptions factors (pCREB), and chaperone proteins (HSP-70). Under these conditions, we noted elevations in both BDNF and pCREB in ADX DR rats compared to the other groups; whereas, HSP-70, was equivalently elevated in ADX-DR and SH-DR groups and was higher than observed in both SH-AL and ADX-AL groups. These results support findings that DR protects hippocampal neurons against KA-induced cellular insult. However, this neuroprotective effect was further enhanced in rats with a lower-than control level of CORT resulting from ADX and maintained by exogenous CORT supplementation. Our results then suggest that DR-induced physiological elevation of GC may have negative functional consequences to DR-induced beneficial effects. These negative effects, however, can be compensated by other DR-produced cellular and molecular protective mechanisms.

Decreased C-Jun Expression Correlates with Impaired Spinal Motoneuron Regeneration in Aged Mice Following Sciatic Nerve Crush

Experimental Gerontology. Feb, 2012  |  Pubmed ID: 22382134

Post-injury nerve regeneration of the peripheral nervous system declines with age, but the mechanisms underlying the weakened axonal regeneration are not well understood. Increased synthesis and activity of the AP-1 transcription factor c-Jun have been implicated in efficient motor axonal regeneration. In the present study, we evaluated the hypothesis that the impaired regenerative capacity in the aged is associated with impaired induction of c-Jun. In non-manipulated young adult or aged mice, no c-Jun and its phosphorylated form were detected in the ventral horn of the spinal cord. Following nerve crush, significant c-Jun and phosphorylated c-Jun occurred in the injured motoneurons of young adult mice, but not in aged animals. In accord with the immunohistochemistry, Western blots also showed that sciatic nerve crush induced c-Jun and its phosphorylation expression in the ventral horn of young adult but not in aged mice. Changes in c-Jun mRNA level detected by in situ hybridization are congruent with that in c-Jun protein content, showing an increase at 5days after crush in young adult but not aged. Moreover, compared with young adult mice, aged mice showed impaired motor axonal regeneration. These results demonstrate that the impaired motor axonal regeneration seen in aged mice is correlated with impaired c-Jun expression and phosphorylation following injury. These data provide a neurobiological explanation for the poor outcome associated with nerve repair in the aged.

Waiting
simple hit counter