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Find video protocols related to scientific articles indexed in Pubmed.
Neurotensinergic Excitation of Dentate Gyrus Granule Cells via G?q-Coupled Inhibition of TASK-3 Channels.
Cereb. Cortex
PUBLISHED: 11-19-2014
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Neurotensin (NT) is a 13-amino acid peptide and serves as a neuromodulator in the brain. Whereas NT has been implicated in learning and memory, the underlying cellular and molecular mechanisms are ill-defined. Because the dentate gyrus receives profound innervation of fibers containing NT and expresses high density of NT receptors, we examined the effects of NT on the excitability of dentate gyrus granule cells (GCs). Our results showed that NT concentration dependently increased action potential (AP) firing frequency of the GCs by the activation of NTS1 receptors resulting in the depolarization of the GCs. NT-induced enhancement of AP firing frequency was not caused indirectly by releasing glutamate, GABA, acetylcholine, or dopamine, but due to the inhibition of TASK-3 K(+) channels. NT-mediated excitation of the GCs was G protein dependent, but independent of phospholipase C, intracellular Ca(2+) release, and protein kinase C. Immunoprecipitation experiment demonstrates that the activation of NTS1 receptors induced the association of G?q/11 and TASK-3 channels suggesting a direct coupling of G?q/11 to TASK-3 channels. Endogenously released NT facilitated the excitability of the GCs contributing to the induction of long-term potentiation at the perforant path-GC synapses. Our results provide a cellular mechanism that helps to explain the roles of NT in learning and memory.
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A critical role for interferon regulatory factor 9 in cerebral ischemic stroke.
J. Neurosci.
PUBLISHED: 09-05-2014
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The failure of past efforts to develop effective stroke treatments is at least partially because these treatments often interfered with essential physiological functions, even though they are targeted toward pathophysiological events, such as inflammation, excitotoxicity, and oxidative stress. Thus, the direct targeting of endogenous neuroprotective or destructive elements holds promise as a potential new approach to treating this devastating condition. Interferon regulatory factor 9 (IRF9), a transcription factor that regulates innate immune responses, has been implicated in neurological pathology. Here, we provide new evidence that IRF9 directly mediates neuronal death in male mice. In response to ischemia/reperfusion (I/R), IRF9 accumulated in neurons. IRF9 deficiency markedly mitigated both poststroke neuronal death and neurological deficits, whereas the neuron-specific overexpression of IRF9 sensitized neurons to death. The histone deacetylase Sirt1 was identified as a novel negative transcriptional target of IRF9 both in vivo and in vitro. IRF9 inhibits Sirt1 deacetylase activity, culminating in the acetylation and activation of p53-mediated cell death signaling. Importantly, both the genetic and pharmacological manipulation of Sirt1 effectively counteracted the pathophysiological effects of IRF9 on stroke outcome. These findings indicate that, rather than activating a delayed innate immune response, IRF9 directly activates neuronal death signaling pathways through the downregulation of Sirt1 deacetylase in response to acute I/R stress.
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Neuronostatin attenuates myocardial contractile function through inhibition of sarcoplasmic reticulum Ca2+-ATPase in murine heart.
Cell. Physiol. Biochem.
PUBLISHED: 06-27-2014
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Neuronostatin, derived from the somatostatin preprohormone, was recently identified to be produced by several tissues exerting a role in cardiovascular regulation and metabolism. Nonetheless, the precise mechanism behind neuronostatin-elicited myocardial responses remains elusive.
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Polyol-mediated C-dot formation showing efficient Tb3+/Eu3+ emission.
Chem. Commun. (Camb.)
PUBLISHED: 06-03-2014
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C-dots (3-5 nm in diameter) obtained by most simple heating of polyols (glycerol, diethylene glycol and PEG 400) show intense blue and green emission (50% quantum yield). Upon modification with TbCl3/EuCl3, energy transfer from the C-dots to the rare-earth metal results in line-type Tb(3+) (green)/Eu(3+) (red) emission with quantum yields up to 85%.
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[Effect of all-trans retinoic acid on cerebral ischemia injury and regulatory T cell accounts in stroke mice].
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi
PUBLISHED: 05-07-2014
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To investigate the cerebral infarct volume 24 hours after transient middle cerebral artery occlusion (tMCAO) and the proportion of CD4?;CD25?;Foxp3?; regulatory T cells (Tregs) in splenocytes in diverse periods after all-trans retinoic acid (ATRA) treatment in mice, so as to explore whether ATRA have the protection against cerebral ischemia damage in mice through intervening Treg differentiation.
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Tumour necrosis factor-? inhibition with lenalidomide alleviates tissue oxidative injury and apoptosis in ob/ob obese mice.
Clin. Exp. Pharmacol. Physiol.
PUBLISHED: 04-08-2014
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Lenalidomide (Revlimid; Selleck Chemicals, Houston, TX, USA), an analogue of thalidomide, possesses potent cytokine modulatory capacity through inhibition of cytokines such as tumour necrosis factor (TNF)-?, a cytokine pivotal for the onset and development of complications in obesity and diabetes mellitus. The present study was designed to evaluate the effect of lenalidomide on oxidative stress, protein and DNA damage in multiple organs in an ob/ob murine model of obesity. To this end, C57BL/6 lean and ob/ob obese mice were administered lenalidomide (50 mg/kg per day, p.o.) for 5 days. Oxidative stress, protein and DNA damage were assessed using the conversion of reduced glutathione (GSH) to oxidized glutathione (GSSG), carbonyl formation and Comet assay, respectively. Apoptosis was evaluated using caspase 3 activity, and levels of Bax, Bcl-2, Bip, caspase 8, caspase 9 and TNF-? were assessed using western blot analysis. Lenalidomide treatment did not affect glucose clearance in lean or ob/ob mice. Obese mice exhibited a reduced GSH/GSSG ratio in the liver, gastrocnemius skeletal muscle and small intestine, as well as enhanced protein carbonyl formation, DNA damage and caspase 3 activity in the liver, kidney, skeletal muscle and intestine; these effects were alleviated by lenalidomide, with the exception of obesity-associated DNA damage in the liver and kidney. Western blot analysis revealed elevated TNF-?, Bax, Bcl-2, Bip, caspase 8 and caspase 9 in ob/ob mice with various degrees of reversal by lenalidomide treatment. Together, these data indicate that lenalidomide protects against obesity-induced tissue injury and protein damage, possibly in association with antagonism of cytokine production and cytokine-induced apoptosis and oxidative stress.
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The Role of SUMO-Conjugating Enzyme Ubc9 in the Neuroprotection of Isoflurane Preconditioning Against Ischemic Neuronal Injury.
Mol. Neurobiol.
PUBLISHED: 03-24-2014
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Preconditioning with volatile anesthetics can create an ischemia tolerance against cerebral ischemia-reperfusion injury. We investigated whether ubiquitin conjugase 9 (Ubc9), the E2 conjugase for SUMOylation, is associated with neuroprotection induced by isoflurane preconditioning (IsoPC). In vitro, Ubc9 protein expression was evaluated at 4 and 24 h after reoxygenation. The role of Ubc9 in the neuroprotective effect was assessed in the presence or absence of Ubc9 small interfering RNA (siRNA). In vivo, rats were preconditionally exposed for 1 h to 2 % isoflurane for five consecutive days followed by middle cerebral artery occlusion. Neurobehavioral scores and infarction volume were determined at different times after reperfusion. The role of Ubc9 in ischemic tolerance was evaluated by intracerebroventricular microinjection with the Ubc9 siRNA. We showed that isoflurane preconditioning improved the cell viability of the SH-SY5Y cells that were challenged by oxygen-glucose deprivation. It also reduced brain infarct volumes and improved neurologic outcomes in the focal cerebral ischemic rat. The expression of Ubc9 was upregulated by isoflurane preconditioning. Knockdown of Ubc9 significantly attenuated the isoflurane preconditioning-induced neuroprotective effects. Isoflurane preconditioning-induced neuroprotection against ischemic injuries is mediated by Ubc9. These results suggest a novel mechanism for isoflurane preconditioning-induced tolerance to cerebral ischemia.
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Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-? signalling.
Clin. Sci.
PUBLISHED: 02-05-2014
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AngII (angiotensin II) is a potent neurohormone responsible for cardiac hypertrophy, in which TGF (transforming growth factor)-? serves as a principal downstream mediator. We recently found that ablation of fibulin-2 in mice attenuated TGF-? signalling, protected mice against progressive ventricular dysfunction, and significantly reduced the mortality after experimental MI (myocardial infarction). In the present study, we investigated the role of fibulin-2 in AngII-induced TGF-? signalling and subsequent cardiac hypertrophy. We performed chronic subcutaneous infusion of AngII in fibulin-2 null (Fbln2-/-), heterozygous (Fbln2+/-) and WT (wild-type) mice by a mini-osmotic pump. After 4 weeks of subpressor dosage of AngII infusion (0.2 ?g/kg of body weight per min), WT mice developed significant hypertrophy, whereas the Fbln2-/- showed no response. In WT, AngII treatment significantly up-regulated mRNAs for fibulin-2, ANP (atrial natriuretic peptide), TGF-?1, Col I (collagen type I), Col III (collagen type III), MMP (matrix metalloproteinase)-2 and MMP-9, and increased the phosphorylation of TGF-?-downstream signalling markers, Smad2, TAK1 (TGF-?-activated kinase 1) and p38 MAPK (mitogen-activated protein kinase), which were all unchanged in AngII-treated Fbln2-/- mice. The Fbln2+/- mice consistently displayed AngII-induced effects intermediate between WT and Fbln2-/-. Pressor dosage of AngII (2 mg/kg of body weight per min) induced significant fibrosis in WT but not in Fbln2-/- mice with comparable hypertension and hypertrophy in both groups. Isolated CFs (cardiac fibroblasts) were treated with AngII, in which direct AngII effects and TGF-?-mediated autocrine effects was observed in WT. The latter effects were totally abolished in Fbln2-/- cells, suggesting that fibulin-2 is essential for AngII-induced TGF-? activation. In conclusion our data indicate that fibulin-2 is essential for AngII-induced TGF-?-mediated cardiac hypertrophy via enhanced TGF-? activation and suggest that fibulin-2 is a potential therapeutic target to inhibit AngII-induced cardiac remodelling.
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Neuroprotective gases--fantasy or reality for clinical use?
Prog. Neurobiol.
PUBLISHED: 01-03-2014
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The neuroprotective properties for certain medical gases have been observed for decades, leading to extensive research that has been widely reported and continues to garner interest. Common gases including oxygen, hydrogen, carbon dioxide and nitric oxide, volatile anesthetics such as isoflurane, sevoflurane, halothane, enflurane and desflurane, non-volatile anesthetics such as xenon and nitrous oxide, inert gases such as helium and argon, and even gases classically considered to be toxic (e.g., hydrogen sulfide and carbon monoxide) have all been supported by the evidence alluding to their use as potential neuroprotective agents. A wide range of neural injury types such as ischemic/hemorrhagic, stroke, subarachnoid hemorrhage, traumatic brain injury, perinatal hypoxic-ischemic brain injuries, neurodegenerative disease as well as spinal cord ischemia have been used as platforms for studying the neuroprotective effects of these gases, yet until now, none of the gases has been widely introduced into clinical use specifically for protection against neural injury. Insufficient clinical data together with contradictory paradigms and results further hinders the clinical trials. However, pre-clinical models suggest that despite the various classes of gases and the broad range of injuries to which medical gases confer, protection, several underlying mechanisms for their neuroprotective properties are similar. In this review, we summarize the literature concerning the neuroprotective effect of each gas and its underlying mechanisms, extract common targets reported for the neuroprotective effects of different gases, highlight the conflicting observations from clinical trials and further discuss the possible hindrances impeding clinical applications in order to propose future research perspectives and therapeutic exploitations.
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Tetramethylpyrazine suppresses transient oxygen-glucose deprivation-induced connexin32 expression and cell apoptosis via the ERK1/2 and p38 MAPK pathway in cultured hippocampal neurons.
PLoS ONE
PUBLISHED: 01-01-2014
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Tetramethylpyrazine (TMP) has been widely used in China as a drug for the treatment of various diseases. Recent studies have suggested that TMP has a protective effect on ischemic neuronal damage. However, the exact mechanism is still unclear. This study aims to investigate the mechanism of TMP mediated ischemic hippocampal neurons injury induced by oxygen-glucose deprivation (OGD). The effect of TMP on hippocampal neurons viability was detected by MTT assay, LDH release assay and apoptosis rate was measured by flow cytometry. TMP significantly suppressed neuron apoptosis in a concentration-dependent manner. TMP could significantly reduce the elevated levels of connexin32 (Cx32) induced by OGD. Knockdown of Cx32 by siRNA attenuated OGD injury. Moreover, our study showed that viability was increased in siRNA-Cx32-treated-neurons, and neuron apoptosis was suppressed by activating Bcl-2 expression and inhibiting Bax expression. Over expression of Cx32 could decrease neurons viability and increase LDH release. Furthermore, OGD increased phosphorylation of ERK1/2 and p38, whose inhibitors relieved the neuron injury and Cx32 up-regulation. Taken together, TMP can reverse the OGD-induced Cx32 expression and cell apoptosis via the ERK1/2 and p38 MAPK pathways.
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Genistein attenuates brain damage induced by transient cerebral ischemia through up-regulation of ERK activity in ovariectomized mice.
Int. J. Biol. Sci.
PUBLISHED: 01-01-2014
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Stroke has severe consequences in postmenopausal women. As replacement therapy of estrogen have various adverse effects and the undermined outcomes. Genistein, a natural phytoestrogen, has been suggested to be a potential neuroprotective agent for such stroke patients. However, the role of genistein and its underlying mechanism in ovariectomized mice has not yet been evaluated. In the present study, ovariectomized mice were treated with genistein (10 mg/kg) or vehicle daily for two weeks before developing transient cerebral ischemia (middle cerebral artery occlusion). The neurological manifestation was evaluated, and infarct volumes were demonstrated by 2,3,5-triphenyltetrazolium chloride staining at 24 h after reperfusion. In addition, phosphorylation of extracellular signal-regulated kinase (ERK) was detected by Western blotting and immunofluorescence staining, and cellular apoptosis was evaluated in the ischemic penumbra. We found that treatment with genistein reduced infarct volumes, improved neurological outcomes and attenuated cellular apoptosis at 24 h after reperfusion. ERK1/2 showed increased phosphorylation by genistein treatment after reperfusion, and an ERK1/2 inhibitor U0126 abolished this protective effect of genistein in terms of infarct volumes, neurological scores and cellular apoptosis. Our findings indicate that treatment with genistein can reduce the severity of subsequent stroke episodes, and that this beneficial function is associated with ERK activation.
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Protective effect of glycyrrhizin, a direct HMGB1 inhibitor, on focal cerebral ischemia/reperfusion-induced inflammation, oxidative stress, and apoptosis in rats.
PLoS ONE
PUBLISHED: 01-01-2014
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Glycyrrhizin (GL) has been reported to protect against ischemia and reperfusion (I/R)-induced injury by inhibiting the cytokine activity of high mobility group box 1 (HMGB1). In the present study, the protective effects of GL against I/R injury, as well as the related molecular mechanisms, were investigated in rat brains.
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Recombinant human thioredoxin-1 promotes neurogenesis and facilitates cognitive recovery following cerebral ischemia in mice.
Neuropharmacology
PUBLISHED: 10-18-2013
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Cerebral ischemia (CI) can induce loss of hippocampal neurons, causing cognitive dysfunction such as learning and memory deficits. In adult mammals, the hippocampal dentate gyrus contains neural stem cells (NSCs) that continuously generate newborn neurons and integrate into the pre-existing networks throughout life, which may ameliorate cognitive dysfunction following CI. Recent studies have demonstrated that recombinant human thioredoxin-1 (rhTrx-1) could promote proliferation of human adipose tissue-derived mesenchymal stem cells and angiogenesis. To investigate whether rhTrx-1 also regulates hippocampal neurogenesis following CI and its underlying mechanisms, adult mice were subjected to bilateral common carotid arteries occlusion (BCCAO) to induce CI and treated with rhTrx-1 before reperfusion. Mice treated with rhTrx-1 showed shortened escape latencies in Morris water maze by 30 days and improvements in spatial memory demonstrated by probe trial test. Enhanced NSCs proliferation was observed at day 14, indicated by BrdU and Ki67 immunostaining. Doublecortin (DCX)(+) cells were also significantly increased following rhTrx-1 treatment. Despite increases in BrdU(+)/NeuN(+) cells by day 30, the double-labeling to total BrdU(+) ratio was not affected by rhTrx-1 treatment. The promotive effects of rhTrx-1 on NSCs proliferation and differentiation were further confirmed in in vitro assays. Western blot revealed increased ERK1/2 phosphorylation after rhTrx-1 treatment, and the ERK inhibitor U0126 abrogated the effects of rhTrx-1 on NSCs proliferation. These results provide initial evidence that rhTrx-1 effects neurogenesis through the ERK signaling pathway and are beneficial for improving spatial learning and memory in adult mice following global CI.
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Inhibition of notch signaling protects mouse lung against zymosan-induced injury.
Shock
PUBLISHED: 06-29-2013
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Notch signaling, a critical pathway in cell fate determination, is well known to be involved in immune and inflammatory reactions, whereas its role in acute lung injury (ALI) remains unclear. Here, we report that notch signal activity is upregulated in lung tissue harvested from an ALI mouse model (induced by zymosan). We showed that notch signal activity in lung tissue was increased 6 h after zymosan injection and peaked at 24 h. Inhibition of notch signaling by either pre- or post-zymosan treatment with N-[N-(3,5-difluorophenacetyl)-l-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) significantly reduced lung injury, characterized by improvement in lung histopathology, lung permeability (protein concentration in bronchoalveolar lavage fluid and lung wet-to-dry weight ratio), lung inflammation (bronchoalveolar lavage fluid cell count, lung myeloperoxidase, and tumor necrosis factor ?), and also alleviated systemic inflammation and tissue damage, thus increasing the 7-day survival rate in zymosan-challenged mice. In conclusion, the role of notch signaling is functionally significant in the development of ALI. Inhibition of notch signaling by pretreatment or posttreatment with DAPT likely exerts its effects in part by mediating the expression of proinflammatory and anti-inflammatory cytokines and influencing tissue neutrophil recruitment. These results also imply that notch inhibitors may help attenuate local inflammatory lung damage.
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Colloidally stable selenium@copper selenide core@shell nanoparticles as selenium source for manufacturing of copper-indium-selenide solar cells.
J Colloid Interface Sci
PUBLISHED: 06-18-2013
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Selenium nanoparticles with diameters of 100-400nm are prepared via hydrazine-driven reduction of selenious acid. The as-prepared amorphous, red selenium (a-Se) particles were neither a stable phase nor were they colloidally stable. Due to phase transition to crystalline (trigonal), grey selenium (t-Se) at or even below room temperature, the particles merged rapidly and recrystallized as micronsized crystal needles. As a consequence, such Se particles were not suited for layer deposition and as a precursor to manufacture thin-film CIS (copper indium selenide/CuInSe2) solar cells. To overcome this restriction, Se@CuSe core@shell particles are presented here. For these Se@CuSe core@shell nanoparticles, the phase transition a-Se?t-Se is shifted to temperatures higher than 100°C. Moreover, a spherical shape of the particles is retained even after phase transition. Composition and structure of the Se@CuSe core@shell nanostructure are evidenced by electron microscopy (SEM/STEM), DLS, XRD, FT-IR and line-scan EDXS. As a conceptual study, the newly formed Se@CuSe core@shell nanostructures with CuSe acting as a protecting layer to increase the phase-transition temperature and to improve the colloidal stability were used as a selenium precursor for manufacturing of thin-film CIS solar cells and already lead to conversion efficiencies up to 3%.
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Hemopexin induces neuroprotection in the rat subjected to focal cerebral ischemia.
BMC Neurosci
PUBLISHED: 05-31-2013
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The plasma protein hemopexin (HPX) exhibits the highest binding affinity to free heme. In vitro experiments and gene-knock out technique have suggested that HPX may have a neuroprotective effect. However, the expression of HPX in the brain was not well elucidated and its expression after cerebral ischemia-reperfusion injury was also poorly studied. Furthermore, no in vivo data were available on the effect of HPX given centrally on the prognosis of focal cerebral ischemia.
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Bombesin facilitates GABAergic transmission and depresses epileptiform activity in the entorhinal cortex.
Hippocampus
PUBLISHED: 05-28-2013
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Bombesin and the bombesin-like peptides including neuromedin B (NMB) and gastrin-releasing peptide (GRP) are important neuromodulators in the brain. We studied their effects on GABAergic transmission and epileptiform activity in the entorhinal cortex (EC). Bath application of bombesin concentration-dependently increased both the frequency and amplitude of sIPSCs recorded from the principal neurons in the EC. Application of NMB and GRP exerted the same effects as bombesin. Bombesin had no effects on mIPSCs recorded in the presence of TTX but slightly depressed the evoked IPSCs. Omission of extracellular Ca(2+) or inclusion of voltage-gated Ca(2+) channel blockers, Cd(2+) and Ni(2+) , blocked bombesin-induced increases in sIPSCs suggesting that bombesin increases GABA release via facilitating extracellular Ca(2+) influx. Bombesin induced membrane depolarization and slightly increased the input resistance of GABAergic interneurons recorded from layer III of the EC. The action potential firing frequency of the interneurons was also increased by bombesin. Bombesin-mediated depolarization of interneurons was unlikely to be mediated by the opening of a cationic conductance but due to the inhibition of inward rectifier K(+) channels. Bath application of bombesin, NMB and GRP depressed the frequency of the epileptiform activity elicited by deprivation of Mg(2+) from the extracellular solution suggesting that bombesin and the bombesin-like peptides have antiepileptic effects in the brain. © 2013 Wiley Periodicals, Inc.
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Different propofol-remifentanil or sevoflurane-remifentanil bispectral index levels for electrocorticographic spike identification during epilepsy surgery.
Anesthesiology
PUBLISHED: 05-08-2013
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Medical therapy, the cornerstone of managing epilepsy, still fails a substantial portion of patients. Little information is available regarding the potential impact of different bispectral index (BIS) levels on electrocorticographic spike identification for surgical epileptic foci resection.
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Cardioprotective effect of remote ischemic postconditioning on children undergoing cardiac surgery: a randomized controlled trial.
Paediatr Anaesth
PUBLISHED: 04-02-2013
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Remote ischemic postconditioning (RPostC) is a noninvasive intervention that has demonstrated cardioprotection and neuroprotection in animal studies.
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A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia.
J. Clin. Invest.
PUBLISHED: 03-21-2013
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Neuropathic pain is characterized by mechanical allodynia induced by low-threshold myelinated A?-fiber activation. The original gate theory of pain proposes that inhibitory interneurons in the lamina II of the spinal dorsal horn (DH) act as "gate control" units for preventing the interaction between innocuous and nociceptive signals. However, our understanding of the neuronal circuits underlying pain signaling and modulation in the spinal DH is incomplete. Using a rat model, we have shown that the convergence of glycinergic inhibitory and excitatory A?-fiber inputs onto PKC?+ neurons in the superficial DH forms a feed-forward inhibitory circuit that prevents A? input from activating the nociceptive pathway. This feed-forward inhibition was suppressed following peripheral nerve injury or glycine blockage, leading to inappropriate induction of action potential outputs in the nociceptive pathway by A?-fiber stimulation. Furthermore, spinal blockage of glycinergic synaptic transmission in vivo induced marked mechanical allodynia. Our findings identify a glycinergic feed-forward inhibitory circuit that functions as a gate control to separate the innocuous mechanoreceptive pathway and the nociceptive pathway in the spinal DH. Disruption of this glycinergic inhibitory circuit after peripheral nerve injury has the potential to elicit mechanical allodynia, a cardinal symptom of neuropathic pain.
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Integrated wall stress: a new methodological approach to assess ventricular workload and myocardial contractile reserve.
J Transl Med
PUBLISHED: 03-21-2013
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Wall stress is a useful concept to understand the progression of ventricular remodeling. We measured cumulative LV wall stress throughout the cardiac cycle over unit time and tested whether this "integrated wall stress (IWS)" would provide a reliable marker of total ventricular workload.
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EMMPRIN is an independent negative prognostic factor for patients with astrocytic glioma.
PLoS ONE
PUBLISHED: 01-29-2013
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Extracellular matrix metalloproteinase inducer (EMMPRIN), also known as CD147, is a member of the immunoglobulin superfamily that is present on the surface of tumor cells and stimulates adjacent fibroblasts to produce matrix metalloproteinases (MMPs). It has been proved to be associated with tumor invasion and metastasis in various human malignancies. In our study, the protein expression level of EMMPRIN in 306 cases of astrocytic glioma is investigated by immunohistochemistry assay. Statistical analysis was utilized to evaluate the association of EMMPRIN with clinicopathological characteristics and prognosis of patients. It was proved that EMMPRIN protein expression was increased in glioma compared with that in normal brain tissue. Moreover, EMMPRIN immunohistochemical staining was correlated with WHO grade and Karnofsky performance score for strong positive EMMPRIN staining is more frequently detected in glioma of advanced grade or low KPS score. It is also demonstrated that EMMPRIN could be an independent negative prognostic factor in glioma for patients with glioma of strong EMMPRIN staining tend to have high risk of death. These results proved that EMMPRIN is associated with prognosis of glioma, which may also suggest the potential role of EMMPRIN in glioma management.
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SirT1 mediates hyperbaric oxygen preconditioning-induced ischemic tolerance in rat brain.
J. Cereb. Blood Flow Metab.
PUBLISHED: 01-09-2013
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Our previous studies have shown that hyperbaric oxygen preconditioning (HBO-PC) induces tolerance to cerebral ischemia/reperfusion (I/R). This study aimed to investigate whether SirT1, a class III histone deacetylase, is involved in neuroprotection elicited by HBO-PC in animal and cell culture models of ischemia. Rats were subjected to middle cerebral artery occlusion for 120?minutes after HBO-PC (once a day for 5 days). Primary cultured cortical neurons were exposed to 2?hours of HBO-PC after 2?hours of oxygen-glucose deprivation (OGD). We showed that HBO-PC increased SirT1 protein and mRNA expression, promoted neurobehavioral score, reduced infarct volume, and improved morphology at 24?hours and 7 days after cerebral I/R. Neuroprotection of HBO-PC was attenuated by SirT1 inhibitor EX527 and SirT1 knockdown by short interfering RNA (siRNA), whereas it was mimicked by SirT1 activator resveratrol. Furthermore, HBO-PC enhanced SirT1 expression and cell viability and reduced lactate dehydrogenase release 24?hours after OGD/re-oxygenation. The neuroprotective effect of HBO-PC was emulated through upregulating SirT1 and, reversely, attenuated through downregulating SirT1. The modulation of SirT1 was made by adenovirus infection carrying SirT1 or SirT1 siRNA. Besides, SirT1 increased B-cell lymphoma 2 (Bcl-2) expression and decrease cleaved caspase 3. These results indicate that SirT1 mediates HBO-PC-induced tolerance to cerebral I/R through inhibition of apoptosis.
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Effects of sevoflurane on self-renewal capacity and differentiation of cultured neural stem cells.
Neurochem. Res.
PUBLISHED: 01-05-2013
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Sevoflurane anesthesia in infant rats can result in long-term cognitive impairment, possibly by inhibiting neurogenesis. The hippocampus is critical for memory consolidation and is one of only two mammalian brain regions where neural stem cells (NSCs) are renewed continuously throughout life. To elucidate the pathogenesis of sevoflurane-induced cognitive dysfunction, we measured the effects of clinical sevoflurane doses on the survival, proliferation, and differentiation of hippocampal NSCs. Neural stem cells were isolated from Sprague-Dawley rat embryos, expanded in vitro, and exposed to sevoflurane at 0.5, 1, or 1.5 minimal alveolar concentration (MAC) for 1 or 6 h. Two days after treatment, cell viability, cytotoxicity, and apoptosis rate were estimated by WST-1 assay, lactate dehydrogenase (LDH) activity, and TdT-mediated dUTP-biotin nick end labeling (TUNEL), respectively, while proliferation rate was assessed by 5-ethynyl-2-deoxyuridine (BrdU) incorporation and Ki67 staining. Differentiation was assayed 7 days after treatment by immunocytochemistry and Western blots of neuron and glial markers. The phosphorylation level of p44/42 extracellular regulated kinases (ERK1/2) was measured in the proliferation and differentiation phases respectively. Sevoflurane at 1 MAC or 1.5 MAC for 1 h increased viable cell number whereas a 6 h exposure at these same concentrations suppressed proliferation and promoted apoptotic death (P < 0.01). Sevoflurane had no effect on NSC differentiation, and a sub-clinical concentration (0.5 MAC) altered neither proliferation nor viability. The phosphorylation level of ERK1/2 increased after 1 h of 1 MAC or 1.5 MAC of sevoflurane exposure in the proliferation phase, but not in the differentiation phase. Brief (1 h) exposure to sevoflurane at clinical concentrations enhanced proliferation of cultured NSCs possibly mediated by ERK1/2, but a 6 h exposure suppressed proliferation and induced apoptosis. Prolonged sevoflurane exposure may decrease the self-renewal capacity of hippocampal NSCs, resulting in cognitive deficits.
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Regulatory T cells are protective in systemic inflammation response syndrome induced by zymosan in mice.
PLoS ONE
PUBLISHED: 01-01-2013
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Systemic inflammation response syndrome (SIRS) is a key and mainly detrimental process in the pathophysiology of multiple organ dysfunction syndrome. The balance of pro-inflammation and anti-inflammation controls the initiation and development of SIRS. However, the endogenous counterregulatory immune mechanisms that are involved in the development of SIRS are not well understood. CD4(+)CD25(+)Foxp3 (forkhead box P3)(+) regulatory T lymphocytes (Treg cells) play a key role in the immunological balance of the body. Thus, our aim was to investigate the contribution of these key immunomodulators (Treg cells) to the immune dysfunction that is observed in zymosan-induced SIRS in mice. We first evaluated the level of Treg cells in the lung of mice 6 h, 1 d, 2 d, 3 d, 5 d, and 7 d after the injection of zymosan or normal saline by western blot, real-time PCR and flow cytometry. We found that the number of Treg cells and the levels of the Treg cell-related transcription factor (Foxp3) and cytokines (IL-10) in the zymosan-treated group significantly decreased on day 1 and day 2 and significantly increased on day 5 compared with the NS-treated group. In the next experiment, the mice were injected with 200 ?g of anti-CD25 mAb (clone PC61) to deplete the Treg cells and then injected with zymosan 2 days later. The number of Treg cells decreased by more than 50% after the injection of the PC61 mAb. In addition, the expression of the anti-inflammatory cytokine IL-10 also decreased. Moreover, the depletion of the Treg cells profoundly increased the micemortality and the degree of lung tissue injury. In conclusion, Treg cells tend to play a protective role in pathogenesis of the zymosan-induced generalized inflammation, and IL-10 signaling is associated with their immunomodulatory effect.
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Adenosinergic depression of glutamatergic transmission in the entorhinal cortex of juvenile rats via reduction of glutamate release probability and the number of releasable vesicles.
PLoS ONE
PUBLISHED: 01-01-2013
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Adenosine is an inhibitory neuromodulator that exerts antiepileptic effects in the brain and the entorhinal cortex (EC) is an essential structure involved in temporal lobe epilepsy. Whereas microinjection of adenosine into the EC has been shown to exert powerful antiepileptic effects, the underlying cellular and molecular mechanisms in the EC have not been determined yet. We tested the hypothesis that adenosine-mediated modulation of synaptic transmission contributes to its antiepileptic effects in the EC. Our results demonstrate that adenosine reversibly inhibited glutamatergic transmission via activation of adenosine A1 receptors without effects on GABAergic transmission in layer III pyramidal neurons in the EC. Adenosine-induced depression of glutamatergic transmission was mediated by inhibiting presynaptic glutamate release probability and decreasing the number of readily releasable vesicles. Bath application of adenosine also reduced the frequency of the miniature EPSCs recorded in the presence of TTX suggesting that adenosine may interact with the exocytosis processes downstream of Ca(2+) influx. Both G?i/o proteins and the protein kinase A pathway were required for adenosine-induced depression of glutamatergic transmission. We further showed that bath application of picrotoxin to the EC slices induced stable epileptiform activity and bath application of adenosine dose-dependently inhibited the epileptiform activity in this seizure model. Adenosine-mediated depression of epileptiform activity was mediated by activation of adenosine A1 receptors and required the functions of G?i/o proteins and protein kinase A pathway. Our results suggest that the depression of glutamatergic transmission induced by adenosine contributes to its antiepileptic effects in the EC.
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Loss of fibulin-2 protects against progressive ventricular dysfunction after myocardial infarction.
J. Mol. Cell. Cardiol.
PUBLISHED: 08-16-2011
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Remodeling of the cardiac extracellular matrix (ECM) is an integral part of wound healing and ventricular adaptation after myocardial infarction (MI), but the underlying mechanisms remain incompletely understood. Fibulin-2 is an ECM protein upregulated during cardiac development and skin wound healing, yet mice lacking fibulin-2 do not display any identifiable phenotypic abnormalities. To investigate the effects of fibulin-2 deficiency on ECM remodeling after MI, we induced experimental MI by permanent coronary artery ligation in both fibulin-2 null and wild-type mice. Fibulin-2 expression was up-regulated at the infarct border zone of the wild-type mice. Acute myocardial tissue responses after MI, including inflammatory cell infiltration and ECM protein synthesis and deposition in the infarct border zone, were markedly attenuated in the fibulin-2 null mice. However, the fibulin-2 null mice had significantly better survival rate after MI compared to the wild-type mice as a result of less frequent cardiac rupture and preserved left ventricular function. Up-regulation of TGF-? signaling and ECM remodeling after MI were attenuated in both ischemic and non-ischemic myocardium of the fibulin-2 null mice compared to the wild type counterparts. Increase in TGF-? signaling in response to angiotensin II was also lessened in cardiac fibroblasts isolated from the fibulin-2 null mice. The studies provide the first evidence that absence of fibulin-2 results in decreased up-regulation of TGF-? signaling after MI and protects against ventricular dysfunction, suggesting that fibulin-2 may be a potential therapeutic target for attenuating the progression of ventricular remodeling.
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Activation of cholinergic anti-inflammatory pathway contributes to the protective effects of 100% oxygen inhalation on zymosan-induced generalized inflammation in mice.
J. Surg. Res.
PUBLISHED: 06-02-2011
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The 100% oxygen inhalation has been demonstrated to have a protective effect on mice with zymosan-induced generalized inflammation. However, the underlying mechanism is largely unknown. The present study was designed to explore the role of the cholinergic anti-inflammatory pathway in this animal model.
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Inhibition of mitochondrial permeability transition pore opening contributes to the neuroprotective effects of ischemic postconditioning in rats.
Brain Res.
PUBLISHED: 06-01-2011
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Ischemic postconditioning (IPost) has been shown to attenuate cerebral ischemia-reperfusion injury. However, the mechanism remains elusive. Because opening of the mitochondrial permeability transition pore (MPTP) is a crucial determinant of cell death after ischemia-reperfusion, we hypothesized that the neuroprotective effect of IPost may be associated with inhibition of MPTP opening. In part 1 of this study, pentobarbital-anesthetized rats subjected to middle cerebral artery occlusion for 90 min, followed by reperfusion for 72 h, were assigned to receive one of the following treatments: three cycles of IPost (15s each), intracerebroventricular injection of saline (control), administration of the MPTP inhibitor cyclosporin A (CsA) (2 ?mol/L, 15 ?L) or its vehicle alcohol, administration of the MPTP opener atractyloside (Atr) (2 mmol/L, 15 ?L), or IPost plus CsA/Atr treatment. Neurological deficit scores (NDS) and infarct volumes were assessed. Mitochondrial ultrastructure and swelling were also examined after reperfusion. In part 2, control and IPost groups underwent ischemia (90 min) and reperfusion (15 min). CsA and Atr groups were treated as described in part 1. Brain mitochondria were isolated after reperfusion and MPTP activity was evaluated. IPost or CsA treatment significantly improved NDS and reduced infarction volume, while Atr reversed the neuroprotective effects of IPost, and attenuated the decrease in mitochondrial swelling induced by IPost or CsA. Thus, inhibiting MPTP opening may play a crucial role in the neuroprotective effects of IPost, which may have potential clinical value against cerebral ischemia-reperfusion injury.
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?2-adrenergic receptor antagonist butoxamine partly abolishes the protection of 100% oxygen treatment against zymosan-induced generalized inflammation in mice.
Shock
PUBLISHED: 05-28-2011
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We have demonstrated that 100% oxygen inhalation is beneficial to zymosan-induced generalized inflammation, and reactive oxygen species may be involved in the protection of oxygen treatment. Other investigators suggest that reactive oxygen species may modulate the sympathetic nervous system activity and ?2-adrenergic receptor (?2AR)-mediated pathway. Moreover, studies have demonstrated that ?2AR agonists are beneficial to sepsis. Therefore, we assessed the effects of ?2AR antagonist butoxamine on the protection of oxygen treatment against zymosan-induced generalized inflammation in mice. Mice were given oxygen treatment by exposure to 100% oxygen for 3 h starting at 4 and 12 h after zymosan injection, respectively. In the mortality study, survival was monitored for 7 days after zymosan injection in mice. At 24 h after zymosan injection, mice were killed, and blood sample and organs were harvested for analysis. We observed that 100% oxygen treatment prevented the abnormal changes in organ histopathology, lactate dehydrogenase and C-reactive protein in serum, inflammatory cytokines in serum and tissue, and arterial blood gas analysis and improved the survival rate in zymosan-challenged mice. We found that pretreatment with ?2AR antagonist butoxamine partly abolished the protection of 100% oxygen inhalation. We also showed that zymosan induced the increase in serum 3-5-cyclic adenosine monophosphate (cAMP) and the decrease in tissue cAMP. However, oxygen treatment increased the cAMP levels in both serum and tissue, which were partly abolished by pretreatment with butoxamine. Thus, 100% oxygen inhalation may protect against zymosan-induced generalized inflammation in mice partly through activation of ?2AR pathway and subsequently enhance cAMP levels in both serum and tissue.
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Intracerebroventricular injection of human prostatic acid phosphatase has potent neuroprotective effects against transient focal cerebral ischemia in rats.
Neurosci. Lett.
PUBLISHED: 05-22-2011
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Though the potential use of adenosine as a neuroprotective agent has long been realized, there are currently no adenosine-based therapies for the prevention or treatment of cerebral ischemia and reperfusion injury. Prostatic acid phosphatase (PAP), an enzyme that has long served as a diagnostic marker for prostate cancer, has been recently demonstrated to exhibit ecto-5-nucleotidase activity, and dephosphorylate endogenous extracellular AMP to adenosine. We therefore tested the hypothesis that PAP has sustained and potent neuroprotective effects against cerebral ischemia in the rat model of middle cerebral artery occlusion. We found that hPAP produced significant neuroprotection against focal cerebral ischemia, as evident from significant reduction in cerebral infarction and neurological deficits. The therapeutic time window for hPAP in rat focal cerebral ischemia model was limited from 6 h before ischemia to 1.5 h after reperfusion. The present study suggested that PAP is a potential candidate for the prevention and treatment of cerebral ischemic injury, especially during perioperative period.
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Reactive oxygen species scavenger inhibits STAT3 activation after transient focal cerebral ischemia-reperfusion injury in rats.
Anesth. Analg.
PUBLISHED: 04-27-2011
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Signal transducer and activator of transcription 3 (STAT3) activation in ischemic brain has been verified. However, the mechanism and the role of STAT3 activation after cerebral ischemia-reperfusion are poorly elucidated. In the present study, we sought to test the hypothesis that STAT3 activation after cerebral ischemia-reperfusion was related to reactive oxygen species (ROS) production.
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Preconditioning with repeated hyperbaric oxygen induces myocardial and cerebral protection in patients undergoing coronary artery bypass graft surgery: a prospective, randomized, controlled clinical trial.
J. Cardiothorac. Vasc. Anesth.
PUBLISHED: 03-15-2011
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To evaluate the cerebral and myocardial protective effects of hyperbaric oxygen preconditioning in both on-pump and off-pump coronary artery bypass graft surgery.
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Autophagy activation is involved in neuroprotection induced by hyperbaric oxygen preconditioning against focal cerebral ischemia in rats.
Brain Res.
PUBLISHED: 03-11-2011
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Our previous studies have demonstrated that hyperbaric oxygen (HBO) preconditioning induces tolerance to focal cerebral ischemia. The present study aimed to investigate whether autophagy is involved in the neuroprotection elicited by HBO preconditioning in a rat model of transient focal cerebral ischemia. Twenty-four hours after the completion of HBO preconditioning (2.5 atm absolute in 100% oxygen for 60 min per day for 5 consecutive days), male Sprague-Dawley rats were subjected to focal cerebral ischemia by middle cerebral artery occlusion (MCAO) for 120 min. The neurobehavioral score and infarct volume were used to evaluate cerebral ischemic injury. An intracerebroventricular injection of the autophagy inhibitor 3-methyladenine (3-MA) or the autophagy inducer rapamycin was administered before HBO preconditioning or MCAO. We found that after reperfusion the protein expression of LC3-II and Beclin 1 and the formation of autophagosomes were increased by HBO preconditioning or ischemia, but the increase following HBO preconditioning was higher than the increase following ischemia. 3-MA suppressed the increases in LC3-II and Beclin 1 induced by HBO preconditioning and attenuated the neuroprotection of HBO preconditioning against cerebral ischemia. Furthermore, 3-MA treatment before MCAO aggravated subsequent cerebral ischemic injury. In contrast, pretreatment with rapamycin up-regulated LC3-II and Beclin 1 after reperfusion and mimicked the neuroprotective effect of HBO preconditioning. These results indicate that HBO preconditioning elevates autophagic activity, which elicits a neuroprotective effect against ischemic injury in the brain, and suggest a novel mechanism of HBO preconditioning-induced tolerance against transient focal cerebral ischemia.
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Sevoflurane preconditioning induces neuroprotection through reactive oxygen species-mediated up-regulation of antioxidant enzymes in rats.
Anesth. Analg.
PUBLISHED: 03-08-2011
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It has been reported that sevoflurane preconditioning can induce neuroprotection, the mechanisms of which, however, are poorly elucidated. We designed the present study to examine the hypothesis that sevoflurane preconditioning could reduce cerebral ischemia- reperfusion injury through up-regulating antioxidant enzyme activities before ischemic injury by generating reactive oxygen species (ROS).
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Beneficial effects of hydrogen gas against spinal cord ischemia-reperfusion injury in rabbits.
Brain Res.
PUBLISHED: 01-04-2011
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Recently, hydrogen gas (H?) is reported to be a new therapeutic agent in organ damage induced by ischemia-reperfusion (I/R). The present study was designed to investigate the beneficial effects of H? against spinal cord I/R injury and its associated mechanisms. Spinal cord ischemia was induced by infrarenal aortic occlusion for 20 min in male New Zealand white rabbits. Treatment with 1%, 2% or 4% H? inhalation was given from 10 min before reperfusion to 60 min after reperfusion (total 70 min). Here, we found that I/R-challenged animals showed significant spinal cord damage characterized by the decreased numbers of normal motor neurons and hind-limb motor dysfunction, which was significantly improved by 2% and 4 % H? treatment. Furthermore, we found that the beneficial effects of H? treatment against spinal cord I/R injury were associated with the decreased levels of oxidative products [8-iso-prostaglandin F2? (8-iso-PGF2?) and malondialdehyde (MDA)] and pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-?) and high-mobility group box 1 (HMGB1)], as well as increased activities of antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)] in serum and spinal cord. In addition, H? treatment reduced motor neuron apoptosis in the spinal cord of this model. Thus, H? inhalation may be an effective therapeutic strategy for spinal cord I/R damage.
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Activation of orexin signal in basal forebrain facilitates the emergence from sevoflurane anesthesia in rat.
Neuropeptides
PUBLISHED: 04-10-2009
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Orexinergic system may play an important role in the regulation of anesthesia-arousal. However, which region or which pathway mediated the effect of orexins was still unclear. In current study, we investigated whether activation of orexin signals in basal forebrain (BF) may alter electroencephalographic activity, induction and emergence time to sevoflurane anesthesia in rats. Either orexin-A or orexin-B was injected into the BF while measuring electroencephalogram (EEG) under 1.0 minimum alveolar concentration (2.4%) sevoflurane anesthesia. The induction and emergence time of sevoflurane anesthesia were measured respectively after an injection of orexin receptor agonist (orexin-A or orexin-B) or antagonist (SB-334867A) into the BF also. We found that the administration of orexin-A (30, 100 pmol) and orexin-B (100 pmol) changed the burst and suppression patterns to arousal EEG in rat under sevoflurane anesthesia. Comparing with orexin-B, injection of lower dose of orexin-A induced more arousal EEG. Intrabasalis microinjection of orexin-A shorted the emergence time, whereas intrabasalis microinjection of SB-334867A (5 microg, 20 microg) delayed the emergence time to sevoflurane anesthesia, without changing anesthetic induction. These findings indicate that the orexin signals in basal forebrain, a middle region of the cholinergic ventral ascending arousal system, plays a crucial role in the anesthesia-arousal regulation.
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Cannabinoid 1 receptor mediation of spinal cord ischemic tolerance induced by limb remote ischemia preconditioning in rats.
J. Thorac. Cardiovasc. Surg.
PUBLISHED: 02-10-2009
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The aim of this study was to examine the influence of endogenous cannabinoids on neuroprotection of the spinal cord afforded by limb remote ischemic preconditioning.
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Ischemic postconditioning protects the spinal cord from ischemia-reperfusion injury via modulation of redox signaling.
J. Thorac. Cardiovasc. Surg.
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It is well known that ischemic postconditioning reduces ischemic-reperfusion injury, but the underlying mechanism is not fully understood. The current study investigated the role of reactive oxygen species-mediated upregulation of endogenous antioxidant enzymes in the generation of a protective effect induced by ischemic postconditioning against spinal cord reperfusion injury in the rabbit.
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Nicotine-induced neuroprotection against ischemic injury involves activation of endocannabinoid system in rats.
Neurochem. Res.
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Nicotine has been reported to exert certain protective effect in the Parkinsons and Alzheimers diseases. Whether it has a similar action in focal cerebral ischemia was unclear. In the present study, rats received either an injection of (-)-nicotine hydrogen tartrate salt (1.2 mg/kg, i.p.) or the vehicle 2 h before the 120 min middle cerebral artery occlusion. Neurological deficits and histological injury were assessed at 24 h after reperfusion. The content of endocannabinoids and the expression of cannabinoid receptor CB1 in brain tissues were determined at different time points after nicotine administration. Results showed that nicotine administration ameliorated neurological deficits and reduced infarct volume induced by cerebral ischemia in the rats. The neuroprotective effect was partially reversed by CB1 blockage. The content of the endocannabinoids N-arachidonylethanolamine and 2-arachidonoylglycerol, as well as the expression of cannabinoid receptor CB1 were up-regulated in brain tissues after nicotine delivery. These results suggest that endogenous cannabinoid system is involved in the nicotine-induced neuroprotection against transient focal cerebral ischemia.
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Neuroprotective effect of calycosin on cerebral ischemia and reperfusion injury in rats.
J Ethnopharmacol
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Radix Astragali has been commonly used as traditional herbal medicine in China for reinforcing vital energy, strengthening superficial resistance and promoting the discharge of pus and the growth of new tissue.
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Activation of canonical notch signaling pathway is involved in the ischemic tolerance induced by sevoflurane preconditioning in mice.
Anesthesiology
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A wealth of evidence has demonstrated that sevoflurane preconditioning induces brain ischemic tolerance, but the mechanism remains poorly understood. This study was designed to investigate the role of canonical Notch signaling in the neuroprotection induced by sevoflurane preconditioning in a mouse model.
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Electroacupuncture improves orthostatic tolerance in healthy individuals via improving cardiac function and activating the sympathetic system.
Europace
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Orthostatic intolerance (OI) is a common clinical problem; however, effective and applicable clinical prevention/treatment is limited. The aim of this study was to investigate whether electroacupuncture (EA) is a novel effective treatment in attenuating OI in healthy individuals.
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Noninvasive limb remote ischemic preconditioning contributes neuroprotective effects via activation of adenosine A1 receptor and redox status after transient focal cerebral ischemia in rats.
Brain Res.
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To investigate whether activation of adenosine A1 receptor (A1R) through limb remote ischemic preconditioning (RIPC) by a noninvasive tourniquet contribute neuroprotective effects against rat focal cerebral ischemic injury induced by transient middle cerebral artery occlusion (MCAO).
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Hyperbaric oxygen preconditioning protects cortical neurons against oxygen-glucose deprivation injury: role of peroxisome proliferator-activated receptor-gamma.
Brain Res.
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Ischemic stroke is one of the leading causes of mortality and disability worldwide. Our previous studies have shown that hyperbaric oxygen (HBO) preconditioning can afford significant neuroprotection against cerebral ischemia-reperfusion (I/R) injury in rats. However, it is still unknown whether HBO preconditioning can directly protect primary cultured cortical neurons against oxygen-glucose deprivation (OGD). Peroxisome proliferator-activated receptor-gamma (PPAR ?) plays a central role in the regulation of apoptosis, oxidative stress and inflammation as well as affords significant neuroprotection against cerebral I/R injury. 15-deoxy-?(12,14)-prostaglandin J(2) (15d-PGJ(2)) is an endogenous ligand with a high affinity for PPAR ?. Recently, some studies demonstrate that activation of PPAR ? mediates lipopolysaccharide and anesthetic preconditioning. In the present study, we firstly found that OGD exposure caused the significant damage of cultured cortical neurons evaluated by cell viability, lactate dehydrogenase (LDH) release and caspase-3 activity, which were significantly ameliorated by HBO preconditioning. Furthermore, HBO preconditioning significantly increased the levels of PPAR ? mRNA and protein, PPAR ? DNA binding activity, 15d-PGJ(2) and antioxidant enzymatic activities in primary cultured cortical neurons with OGD exposure. Moreover, PPAR ? antagonist GW9662 dose-dependently abolished the protection of HBO preconditioning in OGD-exposed neurons. GW9662 blocked the increase of PPAR ? DNA binding activity and antioxidant enzymatic activities, but did not influence the 15d-PGJ(2) level in OGD-exposed neurons with HBO preconditioning. However, the cyclooxygenase (COX)-2 inhibitor NS-398 blocked the production of 15d-PGJ(2) in OGD-exposed neurons with HBO preconditioning. In addition, 15d-PGJ(2) preconditioning could also protect cultured neurons against OGD injury. These results demonstrate that HBO preconditioning has directly beneficial effects on ODG-exposed cortical neurons by the activation of PPAR ? subsequent to the production of 15d-PGJ(2), which in turn increases the downstream antioxidant enzymatic activities.
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TREK1 activation mediates spinal cord ischemic tolerance induced by isoflurane preconditioning in rats.
Neurosci. Lett.
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The aim of this study is to examine the role of one of the two-pore (2P) domain K(+) channels, TREK (TWIK-related K(+) channels, TREK)-1, mediated neuroprotection on spinal cord afforded by isoflurane preconditioning. In Experiment 1, male Sprague-Dawley rats were randomly assigned to control (Con) group, an iso?urane preconditioning (Iso) group, and sham group. Twenty-four hours after the last pretreatment, spinal cord ischemia was induced in Con and Iso groups. Neurobehavioral testing and histopathologic examination were performed after reperfusion. In Experiment 2, the expression of the TREK1 in the spinal cord was assessed by immunohistochemistry, Western blot and real-time polymerase chain reaction. In Experiment 3, Amiloride, a blocker of stretch-sensitive channels, was administered intraperitoneally immediately prior to each isoflurane preconditioning. Iso group showed a significant reductions in motor deficit index as well as increases in the number of normal neurons compared with the Con group. The expression of TREK1 protein and the level of mRNA after ischemia were higher in the rats of the Iso group than those in the Con group. Amiloride pretreatment abolished the protective effects of Iso preconditioning. These finding indicate that isoflurane preconditioning had a neuroprotective effect against spinal cord ischemia reperfusion injury. These effects may be mediated through the TREK1 pathway.
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Protective effect of delayed remote limb ischemic postconditioning: role of mitochondrial K(ATP) channels in a rat model of focal cerebral ischemic reperfusion injury.
J. Cereb. Blood Flow Metab.
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Delayed remote ischemic postconditioning (DRIPost) has been shown to protect the rat brain from ischemic injury. However, extremely short therapeutic time windows hinder its translational use and the mechanism of action remains elusive. Because opening of the mitochondria K(ATP) channel is crucial for cell apoptosis, we hypothesized that the neuroprotective effect of DRIPost may be associated with K(ATP) channels. In the present study, the neuroprotective effects of DRIPost were investigated using adult male Sprague-Dawley rats. Rats were exposed to 90 minutes of middle cerebral artery occlusion followed by 72 hours of reperfusion. Delayed remote ischemic postconditioning was performed with three cycles of bilateral femoral artery occlusion/reperfusion for 5 minutes at 3 or 6 hours after reperfusion. Neurologic deficit scores and infarct volumes were assessed, and cellular apoptosis was monitored by terminal deoxynucleotidyl transferase nick-end labeling. Our results showed that DRIPost applied at 6 hours after reperfusion exerted neuroprotective effects. The K(ATP) opener, diazoxide, protected rat brains from ischemic injury, while the K(ATP) blocker, 5-hydroxydecanote, reversed the neuroprotective effects of DRIPost. These findings indicate that DRIPost reduces focal cerebral ischemic injury and that the neuroprotective effects of DRIPost may be achieved through opening of K(ATP) channels.
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