Synaptic plasticity in hippocampal neurons has been thought to represent a variety of memories. Although accumulating evidence indicates a crucial role of BDNF/TrkB/Akt signaling in the synaptic plasticity of the hippocampus, the mechanism by which Akt, a serine/threonine kinase, controls activity-dependent neuronal plasticity remains unclear. Girdin (also known as APE, GIV, and HkRP1), an actin-binding protein involved both in the remodeling of the actin cytoskeleton and in cell migration, has been identified as a substrate of Akt. Previous studies have demonstrated that deficit of neuronal migration in the hippocampus of Girdin-deficient (Girdin(-/-)) mice is independent on serine phosphorylation of Girdin at S1416 (Girdin S1416) by Akt. In the present study, we focused on the role of Girdin S1416 phosphorylation in BDNF/TrkB/Akt signaling associated with synaptic plasticity. We found that Girdin in the hippocampus was phosphorylated at S1416 in an activity-dependent manner. Phosphorylation-deficient knock-in mice (Girdin(SA/SA) mice), in which S1416 is replaced with alanine, exhibited shrinkage of spines, deficit of hippocampal long-term potentiation, and memory impairment. These phenotypes of Girdin(SA/SA) mice resembled those of Girdin(+/-) mice, which have 50% loss of Girdin expression. Furthermore, Girdin interacted with Src kinase and NR2B subunit of NMDA receptor, leading to phosphorylation of the NR2B subunit and NMDA receptor activation. Our findings suggest that Girdin has two different functions in the hippocampus: Akt-independent neuronal migration and Akt-dependent NR2B phosphorylation through the interaction with Src, which is associated with synaptic plasticity in the hippocampus underlying memory formation.
Blonanserin differs from currently used serotonin 5-HT2A/dopamine-D2 receptor antagonists in that it exhibits higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT2A receptor agonist) and 7-OH-DPAT (a dopamine-D3 receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D1 receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr(197) and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser(897) by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser(896) by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D1-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D3 and serotonin 5-HT2A receptors in the mPFC.Neuropsychopharmacology advance online publication, 17 September 2014; doi:10.1038/npp.2014.207.
Alzheimer's disease (AD), the most common form of dementia among the elderly, is characterized by the progressive decline of cognitive function and has a detrimental impact worldwide. Despite intensive laboratory and clinical research over the last three decades, pharmacological options for the prevention and effective long-term treatment of AD are not currently available. Consequently, successful therapeutic and preventive treatments for AD are needed. When researching materials from natural resources having anti-dementia drug activity, we identified nobiletin, a polymethoxylated flavone from the peel of Citrus depressa. Nobiletin exhibited memory-improving effects in various animal models of dementia and exerted a wide range of beneficial effects against pathological features of AD including amyloid-? (A?) pathology, tau hyperphosphorylation, oxidative stress, cholinergic neurodegeneration and dysfunction of synaptic plasticity-related signaling, suggesting this natural compound could become a novel drug for the treatment and prevention of AD.
Astrocytes are important modulators of the immune and inflammatory reactions in the central nervous system. We have recently demonstrated the role of interferon-induced transmembrane protein 3 (IFITM3) in long-lasting neuronal impairments in mice following neonatal immune challenge by injections of the double-stranded RNA analog polyriboinosinic polyribocytidylic acid. Here, we show that IFITM3 is induced after lipopolysaccharide (LPS) treatment in cultured astrocytes. The induction of IFITM3 by LPS was completely suppressed by the addition of anti-interferon-? (IFN-?) antibody. In addition, neutralization of tumor necrosis factor-? (TNF-?) with its antibody partially inhibited the induction of IFITM3, suggesting that LPS induces IFITM3 through autocrine secretion of IFN-? and TNF-?. Furthermore, experiments using pharmacological inhibitors suggest that LPS induces IFITM3 through activation of TANK-binding kinase 1, p38 mitogen-activated protein kinase, and nuclear factor-?B pathways. Together, these findings may provide new insight into the role of IFITM3 in the pathogenesis of neurodevelopmental diseases associated with immune activation.
This study sought to determine the multicenter reproducibility of magnetic resonance imaging (MRI) and the compatibility of different scanner platforms in assessing carotid plaque morphology and composition. A standardized multi-contrast MRI protocol was implemented at 16 imaging sites (GE: 8; Philips: 8). Sixty-eight subjects (61 ± 8 years; 52 males) were dispersedly recruited and scanned twice within 2 weeks on the same magnet. Images were reviewed centrally using a streamlined semiautomatic approach. Quantitative volumetric measurements on plaque morphology (lumen, wall, and outer wall) and plaque tissue composition [lipid-rich necrotic core (LRNC), calcification, and fibrous tissue] were obtained. Inter-scan reproducibility was summarized using the within-subject standard deviation, coefficient of variation (CV) and intraclass correlation coefficient (ICC). Good to excellent reproducibility was observed for both morphological (ICC range 0.98-0.99) and compositional (ICC range 0.88-0.96) measurements. Measurement precision was related to the size of structures (CV range 2.5-4.9 % for morphology, 36-44 % for LRNC and calcification). Comparable measurement variability was found between the two platforms on both plaque morphology and tissue composition. In conclusion, good to excellent inter-scan reproducibility of carotid MRI can be achieved in multicenter settings with comparable measurement precision between platforms, which may facilitate future multicenter endeavors that use serial MRI to monitor atherosclerotic plaque progression.
Although therapeutic drug monitoring based on blood concentration has been widely implemented in transplant recipients treated with immunosuppressive agents, clinical adverse events such as rejection, infection or drug-induced toxicity caused by inappropriate dosage cannot be completely controlled. Development of an effective assay for optimized immunosuppression would be desirable, which can potentially lead to personalized medicine in renal transplantation. Cyclosporine (CSA) pharmacodynamic analysis using carboxyfluorescein diacetate succinimidyl ester (CFSE)-based T cell proliferation assay was examined in 66 kidney transplant recipients before and after transplantation. Two parameters, the 50% inhibitory concentration (IC50) and the percentage of T-cell proliferation values at the lower plateau (bottom), were compared with clinical events. A significant relation in CSA pharmacodynamic parameters was observed between pre- and post-transplantation. Analysis of the association between clinical outcomes and pharmacodynamic parameters in post-transplant samples demonstrated the following findings: (i) cytomegalovirus (CMV)/varicella zoster virus (VZV) reactivation and CSA-induced nephrotoxicity were significantly associated with high sensitivity to CSA (low bottom or low IC50), (ii) acute T cell-mediated rejection (ATMR) was significantly related to low sensitivity to CSA (high bottom), and (iii) de novo human leukocyte antigen (HLA) antibody production was associated with lower bottom and IC50 values, although the elucidation of those mechanisms is still in progress. It was suggested that CSA pharmacodynamics applied at post-transplantation would be useful for optimizing immunosuppressive therapy.
PurposeIn Japan, biological safety cabinets are commonly used by medical staff to prepare antineoplastic agents. At the Division of Chemotherapy for Outpatients, Nagoya University Hospital, a class II B2 biological safety cabinet is used. The temperature inside this biological safety cabinet decreases in winter. In this study, we investigated the effect of low outside air temperature on the biological safety cabinet temperature, time required to admix antineoplastic agents, and accuracy of epirubicin weight measurement.
Sensory experience regulates the development of various brain structures, including the cortex, hippocampus, and olfactory bulb (OB). Little is known about how sensory experience regulates the dendritic spine development of OB interneurons, such as granule cells (GCs), although it is well studied in mitral/tufted cells. Here, we identify a transcription factor, Npas4, which is expressed in OB GCs immediately after sensory input and is required for dendritic spine formation. Npas4 overexpression in OB GCs increases dendritic spine density, even under sensory deprivation, and rescues reduction of dendrite spine density in the Npas4 knockout OB. Furthermore, loss of Npas4 upregulates expression of the E3-ubiquitin ligase Mdm2, which ubiquitinates a microtubule-associated protein Dcx. This leads to reduction in the dendritic spine density of OB GCs. Together, these findings suggest that Npas4 regulates Mdm2 expression to ubiquitinate and degrade Dcx during dendritic spine development in newborn OB GCs after sensory experience.
The aim of this study is to investigate the inter-scan reproducibility of kinetic parameters in atherosclerotic plaque using dynamic contrast-enhanced (DCE) cardiovascular magnetic resonance (CMR) in a multi-center setting at 3T.
Disrupted-in-schizophrenia-1 (DISC1) has been widely associated with several psychiatric disorders, including schizophrenia, mood disorders and autism. We previously reported that a deficiency of DISC1 may induce low anxiety and/or high impulsivity in mice with disruption of exons 2 and 3 of the Disc1 gene (Disc1(?2-3/?2-3)). It remains unclear, however, if deficiency of DISC1 leads to specific alterations in distinct neuronal systems. In the present study, to understand the role of DISC1 in ?-aminobutyric acid (GABA) interneurons and mesocorticolimbic dopaminergic (DAergic) neurons, we investigated the number of parvalbumin (PV)-positive interneurons, methamphetamine (METH)-induced DA release and the expression levels of GABAA, DA transporter (DAT) and DA receptors in wild-type (Disc1(+/+)) and Disc1(?2-3/?2-3) mice. Female Disc1(?2-3/?2-3) mice showed a significant reduction of PV-positive interneurons in the hippocampus, while no apparent changes were observed in mRNA expression levels of GABAA receptor subunits. METH-induced DA release was significantly potentiated in the nucleus accumbens (NAc) of female Disc1(?2-3/?2-3) mice, although there were no significant differences in the expression levels of DAT. Furthermore, the expression levels of DA receptor mRNA were upregulated in the NAc of female Disc1(?2-3/?2-3) mice. Male Disc1(?2-3/?2-3) mice showed no apparent differences in all experiments. DISC1 may play a critical role in gender-specific developmental alteration in GABAergic inhibitory interneurons and DAergic neurons.
Increasing epidemiological evidence indicates that prenatal infection and childhood central nervous system infection with various viral pathogens enhance the risk for several neuropsychiatric disorders. Polyriboinosinic-polyribocytidilic acid (polyI:C) is known to induce strong innate immune responses that mimic immune activation by viral infections. Our previous findings suggested that activation of the innate immune system in astrocytes results in impairments of neurite outgrowth and spine formation, which lead to behavioral abnormalities in adulthood. To identify candidates of astrocyte-derived humoral factors that affect neuronal development, we analyzed astrocyte-conditioned medium (ACM) from murine astrocyte cultures treated with polyI:C (polyI:C-ACM) by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Through a quantitative proteomic screen, we found that 13 protein spots were differentially expressed compared with ACM from vehicle-treated astrocytes (control-ACM), and characterized one of the candidates, matrix metalloproteinase-3 (Mmp3). PolyI:C treatment significantly increased the expression levels of Mmp3 mRNA and protein in astrocytes, but not microglia. PolyI:C-ACM was associated with significantly higher Mmp3 protein level and enzyme activity than control-ACM. The addition of recombinant Mmp3 into control-ACM impaired dendritic elongation of primary cultured hippocampal neurons, while the deleterious effect of polyI:C-ACM on neurite elongation was attenuated by knockdown of Mmp3 in astrocytes. These results suggest that Mmp3 is a possible mediator of polyI:C-ACM-induced neurodevelopmental impairment.
Molecular hydrogen (H2) scavenges hydroxyl radicals. Recently, H2 has been reported to prevent a variety of diseases associated with oxidative stress in model systems and in humans. Here, we studied the effects of H2 on rat fetal hippocampal damage caused by ischemia and reperfusion (IR) on day 16 of pregnancy with the transient occlusion of the bilateral utero-ovarian arteries. Starting 2 days before the operation, we provided the mothers with hydrogen-saturated water ad libitum until vaginal delivery. We observed a significant increase in the concentration of H2 in the placenta after the oral administration of hydrogen-saturated water to the mothers, with less placental oxidative damage after IR in the presence of H2. Neonatal growth retardation was observed in the IR group, which was alleviated by the H2 administration. We analyzed the neuronal cell damage in the CA1 and CA3 areas of the hippocampus at day 7 after birth by immunohistochemical analysis of the 8-oxo-7,8-dihydro-2?-deoxyguanosine- and 4-hydroxy-2-nonenal-modified proteins. Both oxidative stress markers were significantly increased in the IR group, which was again ameliorated by the H2 intake. Last, 8-week-old rats were subjected to a Morris water maze test. Maternal H2 administration improved the reference memory of the offspring to the sham level after IR injury during pregnancy. Overall, the present results support the idea that maternal H2 intake helps prevent the hippocampal impairment of offspring induced by IR during pregnancy.
The mechanisms of drug resistance in cancer are not fully elucidated. To study the drug resistance of gastric cancer, we analyzed gene expression and DNA methylation profiles of 5-fluorouracil (5-FU)- and cisplatin (CDDP)-resistant gastric cancer cells and biopsy specimens. Drug-resistant gastric cancer cells were established with culture for >10 months in a medium containing 5-FU or CDDP. Endoscopic biopsy specimens were obtained from gastric cancer patients who underwent chemotherapy with oral fluoropyrimidine S-1 and CDDP. Gene expression and DNA methylation analyses were performed using microarray, and validated using real-time PCR and pyrosequencing, respectively. Out of 17,933 genes, 541 genes commonly increased and 569 genes decreased in both 5-FU- and CDDP-resistant AGS cells. Genes with expression changed by drugs were related to GO term 'extracellular region' and 'p53 signaling pathway' in both 5-FU- and CDDP-treated cells. Expression of 15 genes including KLK13 increased and 12 genes including ETV7 decreased, in both drug-resistant cells and biopsy specimens of two patients after chemotherapy. Out of 10,365 genes evaluated with both expression microarray and methylation microarray, 74 genes were hypermethylated and downregulated, or hypomethylated and upregulated in either 5-FU-resistant or CDDP-resistant cells. Of these genes, expression of 21 genes including FSCN1, CPT1C and NOTCH3, increased from treatment with a demethylating agent. There are alterations of gene expression and DNA methylation in drug-resistant gastric cancer; they may be related to mechanisms of drug resistance and may be useful as biomarkers of gastric cancer drug sensitivity.
Accumulating evidence suggests that dysregulation of histone modification is involved in the pathogenesis and/or pathophysiology of psychiatric disorders. However, the abnormalities in histone modification in the animal model of schizophrenia and the efficacy of antipsychotics for such abnormalities remain unclear. Here, we investigated the involvement of histone modification in phencyclidine-induced behavioral abnormalities and the effects of antipsychotics on these abnormalities. After repeated phencyclidine (10 mg/kg) treatment for 14 consecutive days, mice were treated with antipsychotics (clozapine or haloperidol) or the histone deacetylase inhibitor sodium butyrate for 7 d. Repeated phencyclidine treatments induced memory impairment and social deficit in the mice. The acetylation of histone H3 at lysine 9 residues decreased in the prefrontal cortex with phencyclidine treatment, whereas the expression level of histone deacetylase 5 increased. In addition, the phosphorylation of Ca2+/calmodulin-dependent protein kinase II in the nucleus decreased in the prefrontal cortex of phencyclidine-treated mice. These behavioral and epigenetic changes in phencyclidine-treated mice were attenuated by clozapine and sodium butyrate but not by haloperidol. The dopamine D1 receptor antagonist SCH-23390 blocked the ameliorating effects of clozapine but not of sodium butyrate. Furthermore, clozapine and sodium butyrate attenuated the decrease in expression level of GABAergic system-related genes in the prefrontal cortex of phencyclidine-treated mice. These findings suggest that the antipsychotic effect of clozapine develops, at least in part, through epigenetic modification by activation of the dopamine D1 receptor in the prefrontal cortex.
In a previous report, we identified a novel molecule, SHATI/NAT8L, having an inhibitory effect on methamphetamine (METH)-induced hyperlocomotion, sensitization, and conditioned place preference (CPP). SHATI/NAT8L attenuates the METH-induced increase in dopamine overflow in the nucleus accumbens (NAc) by promoting plasmalemmal and vesicular dopamine uptake. However, the biological functions of the protein remain unclear. In this study, we explored NAT8L-binding proteins using pull-down assays and identified a number of components of the adaptor protein (AP)-2 complex, which is a multimeric protein localized to the plasma membrane that functions to internalize cargo during clathrin-mediated endocytosis. To investigate whether NAT8L regulates the receptor localization to the cell surface, cell-surface dopamine D1 receptor in the NAc of Nat8l knockout (KO) mice was quantified. We found that dopamine D1 receptor on the cell surface was increased in the NAc of Nat8l KO mice compared with the wild type (WT) animals. Consistent with this finding, Nat8l KO mice showed higher basal locomotor activity and heightened sensitivity to D1 agonist compared with WT mice. In addition, METH-induced sensitization and CPP were enhanced in Nat8l KO mice. These results suggest that NAT8L might regulate the localization of cell-surface dopamine D1 receptor, thereby controlling basal behaviour and sensitivity to METH. Furthermore, we observed a single nucleotide polymorphism (SNP) in the human NAT8L gene related to reward dependence, a personality trait, and grey matter volume in the caudate nucleus in healthy subjects, suggesting that NAT8L might also affect human personality.
Gestational nicotine exposure is associated with cognitive abnormalities in young offspring. However, practical strategies for prevention or treatment of impaired cognitive behaviors of offspring are not available due to the lack of systematic investigation of underlying mechanism. Therefore, this study aimed at examining the effects of gestational and/or perinatal nicotine exposure (GPNE) on cognitive behaviors in offspring of C57BL/6J mice to provide systematic behavioral data. Pregnant mice were exposed to nicotine via sweetened drinking water during six time-windows, including gestational day 0 to day 13 (G0-G13), G14-postnatal day 0 (P0), G0-P0, G14-P7, G0-P7, and P0-P7. During P42-P56 days, both male and female offspring were given a battery of behavioral tests. Depending on the time of exposure, GPNE impaired working memory, object-based attention, and prepulse inhibition in male and female offspring to different extents. Nicotine exposure during G14-P0 also decreased norepinephrine turnover in the prefrontal cortex on P28 and P56. Overall results indicate that nicotine exposure during any time-windows of development impairs cognitive behaviors in offspring, and suggest that certain time-windows, e.g., G14-P0, should be selected for further studies on the underlying neurochemical or molecular mechanisms.
Senescence-accelerated mouse prone 8 (SAMP8) is a model of aging characterized by the early onset of learning and memory impairment and various pathological features of Alzheimers disease (AD). Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, ameliorates learning and memory impairment in olfactory-bulbectomized mice, amyloid precursor protein transgenic mice, and NMDA receptor antagonist-treated mice. Here, we present evidence that this natural compound improves age-related cognitive impairment and reduces oxidative stress and tau phosphorylation in SAMP8 mice. Treatment with nobiletin (10 or 50mg/kg) reversed the impairment of recognition memory and context-dependent fear memory in SAMP8 mice. Treatment with nobiletin also restored the decrease in the GSH/GSSG ratio in the brain of SAMP8 mice. In addition, increases in glutathione peroxidase and manganese-superoxide dismutase activities, as well as a decrease in protein carbonyl level, were observed in the brain of nobiletin-treated SAMP8 mice. Furthermore, nobiletin reduced tau phosphorylation in the hippocampus of SAMP8 mice. Together, the markedly beneficial effects of nobiletin represent a potentially useful treatment for ameliorating the learning and memory deficits, oxidative stress, and hyperphosphorylation of tau in aging as well as age-related neurodegenerative diseases such as AD.
Voriconazole is a triazole antifungal agent with potent activity against a broad spectrum of pathogens, including Aspergillus and Candida species. In human adults, allelic polymorphisms of CYP2C19 are known to correlate with significant variation in voriconazole plasma concentration. Here, we report an analysis of CYP2C19 phenotype and voriconazole plasma concentrations in children.
Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) remodel the pericellular environment by regulating the cleavage of extracellular matrix proteins, cell surface components, neurotransmitter receptors, and growth factors, which together regulate cell adhesion, synaptogenesis, synaptic plasticity, and long-term potentiation. Increased MMP activity and dysregulation of the balance between MMPs and TIMPs have also been implicated in various pathological conditions. Recent studies have suggested that prolonged seizures are associated with high MMP levels in serum and neural tissues, and certain extracellular macromolecule targets may influence the pathogenesis of epilepsy and seizure. In this review, we discuss the roles of MMP activation in animal models of epilepsy.
Cumulative incidences of multiple risk factors are related to pathology of psychiatric disorders. The present study was designed to examine combinative effects of a neonatal immune challenge with adolescent abused substance treatment on the psychological behaviors and molecular expressions in the adult. C57BL/6J mice were neonatally treated, with polyriboinosinic-polyribocytidylic acid (PolyI:C: 5mg/kg) during postnatal days (PD) 2-6, then with phencyclidine (PCP: 10mg/kg) during adolescence (PD35-41). Locomotor activity was analyzed to evaluate sensitivity to PCP on PD35 and PD41. Emotional and cognitive tests were carried out on PD42-48. Neonatal PolyI:C treatment markedly enhanced sensitivity to PCP- and methamphetamine-induced hyperactivity in the adolescent. Mice treated with both neonatal PolyI:C and adolescent PCP (PolyI:C/PCP) showed social deficit and object recognition memory impairment. The expression of glutamate/aspartate transporter (GLAST) in the prefrontal cortex (PFC) was significantly increased in the (PolyI:C/PCP)-treated mice. Infusion of glutamate transporter inhibitor (DL-TBOA: 1nmol/bilaterally) into the PFC reversed the object recognition impairment in the (PolyI:C/PCP)-treated mice. These results indicate that the combined treatment of neonatal PolyI:C with adolescent PCP leads to behavioral abnormalities, which were associated with increase of GLAST expression in the adult PFC.
Relapse of drug abuse after abstinence is a major challenge to the treatment of addicts. In our well-established mouse models of methamphetamine (Meth) self-administration and reinstatement, bilateral microinjection of adeno-associated virus vectors expressing GDNF (AAV-Gdnf) into the striatum significantly reduced Meth self-administration, without affecting locomotor activity. Moreover, the intrastriatal AAV-Gdnf attenuated cue-induced reinstatement of Meth-seeking behaviour in a sustainable manner. In addition, this manipulation showed that Meth-primed reinstatement of Meth-seeking behaviour was reduced. These findings suggest that the AAV vector-mediated Gdnf gene transfer into the striatum is an effective and sustainable approach to attenuate Meth self-administration and Meth-associated cue-induced relapsing behaviour and that the AAV-mediated Gdnf gene transfer in the brain may be a valuable gene therapy against drug dependence and protracted relapse in clinical settings.
We previously identified a new molecule, "SHATI/NAT8L," which has an inhibitory effect on methamphetamine (METH)-induced hyperlocomotion, sensitization, and conditioned place preference. Nevertheless, the extent of SHATI localization and its functions are only partially understood. In this study, we used the FLAG-tag method to investigate SHATI localization. We found that SHATI was localized to microtubules when expressed in COS7 cells and cortical primary neurons. This distribution of SHATI was less apparent after cells were treated with colchicine, a tubulin polymerization inhibitor that disrupts the microtubule structure. This finding suggests that SHATI is associated with microtubule structure. Interestingly, overexpression of SHATI in COS7 cells could attenuate the colchicine-induced decrease in acetylated microtubules, indicating that SHATI plays a role in stabilizing microtubules. Furthermore, we showed that Shati deletion impaired neurite elongation. In cortical primary neurons, neurite length and complexity in Shati-knockout (KO) mice were significantly decreased. In pyramidal neurons in the prefrontal cortex, dendrite length and complexity were also significantly decreased in Shati-KO mice compared with wild-type mice. These results suggest a novel function for SHATI, which may be a new member of the microtubule-associated protein family.
Interferon-induced transmembrane protein 3 (IFITM3) ?plays a crucial role in the antiviral responses of Type I interferons (IFNs). The role of IFITM3 in the central nervous system (CNS) is, however, largely unknown, despite the fact that its expression is increased in the brains of patients with neurologic and neuropsychiatric diseases. Here, we show the role of IFITM3 in long-lasting neuronal impairments in mice following polyriboinosinic-polyribocytidylic acid (polyI:C, a synthetic double-stranded RNA)-induced immune challenge during the early stages of development. We found that the induction of IFITM3 expression in the brain of mice treated with polyI:C was observed only in astrocytes. Cultured astrocytes were activated by polyI:C treatment, leading to an increase in the mRNA levels of inflammatory cytokines as well as Ifitm3. When cultured neurons were treated with the conditioned medium of polyI:C-treated astrocytes (polyI:C-ACM), neurite development was impaired. These polyI:C-ACM-induced neurodevelopmental abnormalities were alleviated by ifitm3(-/-) astrocyte-conditioned medium. Furthermore, decreases of MAP2 expression, spine density, and dendrite complexity in the frontal cortex as well as memory impairment were evident in polyI:C-treated wild-type mice, but such neuronal impairments were not observed in ifitm3(-) (/) (-) mice. We also found that IFITM3 proteins were localized to the early endosomes of astrocytes following polyI:C treatment and reduced endocytic activity. These findings suggest that the induction of IFITM3 expression in astrocytes by the activation of the innate immune system during the early stages of development has non-cell autonomous effects that affect subsequent neurodevelopment, leading to neuropathological impairments and brain dysfunction, by impairing endocytosis in astrocytes.
The aim of this retrospective study was to determine the prevalence of silent coronary artery disease (CAD) and the risk factors associated with concomitant CAD in Japanese patients undergoing carotid artery stenting (CAS).
During the development of addiction, addictive drugs induce transient and long-lasting changes in the brain including expression of endogenous molecules and alteration of morphological structure. Of the altered endogenous molecules, some facilitate but others slow the development of drug addiction. Previously, we have reported that tumor necrosis factor alpha (TNF-?) is a critical molecule among endogenous anti-addictive modulators using animal models of drug-conditioned place preference and drug discrimination.
In the present study, we investigated whether counseling at an outpatient asthma clinic improved asthma symptoms, adherence and patient satisfaction: The asthma control test (ACT) and asthma control questionnaire (ACQ) were used to assess subjective symptoms, 10-item version of the drug attitude inventory (DAI-10) was used to determine medication adherence, and 8-item Japanese version of the client satisfaction questionnaire (CSQ-8J) was used to ascertain patient satisfaction. All scores of inhalation technique, PEF (peak expiratory flow) value/predicted PEF value (%), ACT, ACQ and DAI-10 in 26 patients with asthma increased after counseling at the outpatient asthma clinic compared to those before counseling. The average CSQ-8J score of 28 points (highest possible score: 32 points) indicated that the patients were satisfied with services provided by this clinic. These results indicate that counseling provided by pharmacists at the outpatient clinic is a valuable way improving subjective symptoms, lung function and medication adherence. These results also indicate that counseling at the asthma clinic by pharmacists improves the quality of life of patients with asthma.
Schizophrenia affects nearly 1% of the population and is clinically characterized by positive symptoms (e.g. delusions and hallucinations), negative symptoms (e.g. affective flattening, apathy and social withdrawal) and cognitive dysfunction. Genetic susceptibility factors for schizophrenia, such as neuregulinl, dysbindin and disrupted-in-schizophrenia 1 (DISC1), have recently been reported, some of which play a role in neurodevelopment. Furthermore, epidemiologic studies suggest that environmental insults, such as prenatal infection and perinatal complication, are involved in the development of schizophrenia. The possible interaction between environment and genetic susceptibility factors is proposed as a promising disease etiology of schizophrenia. Polyriboinosinic-polyribocytidylic acid (polyI:C), a toll-like receptor 3 ligand, induces a strong innate immune response. Maternal immune activation by polyI:C exposure in rodents induces a wide spectrum of behavioral and neurochemical abnormalities in adult offspring. We have reported that neonatal injection of polyI:C in mice results in schizophrenia-like behavioral abnormalities in adulthood. In this review, we show how gene-environment interactions during neurodevelopment result in phenotypic changes in adulthood, by injecting polyI:C into transgenic mice that express a dominant-negative form of human DISC1 (DN-DISC1). Our findings suggest that polyI:C-treated DN-DISC1 mice are a validated animal model for schizophrenia with gene-environment interactions.
Recurrent seizure activity has been shown to induce a variety of permanent structural changes in the brain. Matrix metalloproteinases (MMPs) function to promote neuronal plasticity, primarily through cleavage of extracellular matrix proteins. Here, we investigated the role of MMP-9 in the development of pentylenetetrazole (PTZ)-induced kindled seizure in mice. Repeated treatment with PTZ (40 mg/kg) produced kindled seizure, which was accompanied by enhanced MMP-9 activity and expression in the hippocampus. No change in MMP-9 activity was observed in the hippocampi of mice with generalized tonic seizure following single administration of PTZ (60 mg/kg). MMP-9 colocalized with the neuronal marker NeuN and the glial marker GFAP in the dentate gyrus of the kindled mouse hippocampus. Coadministration of diazepam or MK-801 with PTZ inhibited the development of kindling and the increased MMP-9 levels in the hippocampus. Marked suppression of kindled seizure progression in response to repeated PTZ treatment was observed in MMP-9((-/-)) mice compared with wild-type mice, an observation that was accompanied by decreased hippocampal levels of mature brain-derived neurotrophic factor. Microinjecting the BDNF scavenger TrkB-Fc into the right ventricle before each PTZ treatment significantly suppressed the development of kindling in wild-type mice, whereas no effect was observed in MMP-9((-/-)) mice. On the other hand, bilateral injections of pro-BDNF into the hippocampal dentate gyrus significantly enhanced kindling in wild-type mice but not MMP-9((-/-)) mice. These findings suggest that MMP-9 is involved in the progression of behavioral phenotypes in kindled mice because of conversion of pro-BDNF to mature BDNF in the hippocampus.
Disrupted-In-Schizophrenia 1 (DISC1) is a promising candidate gene for susceptibility to psychiatric disorders, including schizophrenia. DISC1 appears to be involved in neurogenesis, neuronal migration, axon/dendrite formation and synapse formation; during these processes, DISC1 acts as a scaffold protein by interacting with various partners. However, the lack of Disc1 knockout mice and a well-characterized antibody to DISC1 has made it difficult to determine the exact role of DISC1 in vivo. In this study, we generated mice lacking exons 2 and 3 of the Disc1 gene and prepared specific antibodies to the N- and C-termini of DISC1. The Disc1 mutant mice are viable and fertile, and no gross phenotypes, such as disorganization of the brains cytoarchitecture, were observed. Western blot analysis revealed that the DISC1-specific antibodies recognize a protein with an apparent molecular mass of ~100 kDa in brain extracts from wild-type mice but not in brain extracts from DISC1 mutant mice. Immunochemical studies demonstrated that DISC1 is mainly localized to the vicinity of the Golgi apparatus in hippocampal neurons and astrocytes. A deficiency of full-length Disc1 induced a threshold shift in the induction of long-term potentiation in the dentate gyrus. The Disc1 mutant mice displayed abnormal emotional behavior as assessed by the elevated plus-maze and cliff-avoidance tests, thereby suggesting that a deficiency of full-length DISC1 may result in lower anxiety and/or higher impulsivity. Based on these results, we suggest that full-length Disc1-deficient mice and DISC1-specific antibodies are powerful tools for dissecting the pathophysiological functions of DISC1.
Methamphetamine (METH) is a highly addictive drug, and addiction to METH has increased to epidemic proportions worldwide. Chronic use of METH causes psychiatric symptoms, such as hallucinations and delusions, and long-term cognitive deficits, which are indistinguishable from paranoid schizophrenia. The GABA receptor system is known to play a significant role in modulating the dopaminergic neuronal system, which is related to behavioral changes induced by drug abuse. However, few studies have investigated the effects of GABA receptor agonists on cognitive deficits induced by METH. In the present review, we show that baclofen, a GABA receptor agonist, is effective in treating METH-induced impairment of object recognition memory and prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating in mice. Acute and repeated treatment with METH induced a significant impairment of PPI. Furthermore, repeated but not acute treatment of METH resulted in a long-lasting deficit of object recognition memory. Baclofen, a GABA(B) receptor agonist, dose-dependently ameliorated the METH-induced PPI deficits and object recognition memory impairment in mice. On the other hand, THIP, a GABA(A) receptor agonist, had no effect on METH-induced cognitive deficits. These results suggest that GABA(B) receptors may constitute a putative new target in treating cognitive deficits in chronic METH users.
Schizophrenia is a devastating psychiatric disorder that impairs mental and social functioning and affects approximately 1% of the population worldwide. Genetic susceptibility factors for schizophrenia have recently been reported, some of which are known to play a role in neurodevelopment; these include neuregulin-1, dysbindin, and disrupted-in-schizophrenia 1 (DISC1). Moreover, epidemiologic studies suggest that environmental insults, such as prenatal infection and perinatal complication, are involved in the development of schizophrenia. The possible interaction between environment and genetic susceptibility factors, especially during neurodevelopment, is proposed as a promising disease etiology of schizophrenia. Polyriboinosinic-polyribocytidilic acid (polyI : C) is a synthetic analogue of double-stranded RNA that leads to the pronounced but time-limited production of pro-inflammatory cytokines. Maternal immune activation by polyI : C exposure in rodents is known to precipitate a wide spectrum of behavioral, cognitive, and pharmacological abnormalities in adult offspring. Recently, we have reported that neonatal injection of polyI : C in mice results in schizophrenia-like behavioral alterations in adulthood. In this review, we show how gene-environment interactions during neurodevelopment result in phenotypic changes in adulthood by injecting polyI : C into transgenic mice that express a dominant-negative form of human DISC1 (DN-DISC1). Our findings suggest that polyI : C-treated DN-DISC1 mice are a well-validated animal model for schizophrenia that reflects gene-environment interactions.
Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) remodel the pericellular environment by regulating the cleavage of extracellular matrix proteins, cell surface components, neurotransmitter receptors, and growth factors that mediate cell adhesion, synaptogenesis, synaptic plasticity, and long-term potentiation. Interestingly, increased MMP activity and dysregulation of the balance between MMPs and TIMPs have also been implicated in various pathologic conditions. In this paper, we discuss various animal models that suggest that the activation of the gelatinases MMP-2 and MMP-9 is involved in pathogenesis of drug dependence, Alzheimers disease, and epilepsy.
A major disadvantage of carotid artery stenting (CAS) compared to carotid endarterectomy is the increased risk of cerebral embolism. Thus, establishing a simple method to discriminate fragile plaques on preoperative routine examination is important. The present study examined whether high-intensity signal (HIS) in the plaque on time-of-flight (TOF) MRA, performed for screening, can discriminate plaque at high risk for cerebral embolism during CAS.
Patients with locally advanced head and neck cancer were treated with concurrent chemoradiotherapy using three courses of cisplatin. However, many patients were unable to complete the scheduled cisplatin treatment due to adverse effects. The objective of this study was to retrospectively elucidate the source of the low completion rate of cisplatin courses.
The cholinesterase inhibitor, rivastigmine, ameliorates cognitive dysfunction and is approved for the treatment of Alzheimers disease (AD). Rivastigmine is a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE); however, the impact of BuChE inhibition on cognitive dysfunction remains to be determined. We compared the effects of a selective BuChE inhibitor, N1-phenethyl-norcymserine (PEC), rivastigmine and donepezil (an AChE-selective inhibitor) on cognitive dysfunction induced by amyloid-? peptide (A?(1-40)) in mice. Five-week-old imprinting control region (ICR) mice were injected intracerebroventricularly (i.c.v.) with either A?(1-40) or the control peptide A?(40-1) on Day 0, and their recognition memory was analyzed by a novel object recognition test. Treatment with donepezil (1.0mg/kg), rivastigmine (0.03, 0.1, 0.3mg/kg) or PEC (1.0, 3.0mg/kg) 20min prior to, or immediately after the acquisition session (Day 4) ameliorated the A?(1-40) induced memory impairment, indicating a beneficial effect on memory acquisition and consolidation. In contrast, none of the investigated drugs proved effective when administrated before the retention session (Day 5). Repeated daily administration of donepezil, rivastigmine or PEC, on Days 0-3 inclusively, ameliorated the cognitive dysfunction in A?(1-40) challenged mice. Consistent with the reversal of memory impairments, donepezil, rivastigmine or PEC treatment significantly reduced A?(1-40) induced tyrosine nitration of hippocampal proteins, a marker of oxidative damage. These results indicate that BuChE inhibition, as well as AChE inhibition, is a viable therapeutic strategy for cognitive dysfunction in AD.
Atrial natriuretic peptide (ANP) was recently reported to ameliorate fibrosis in the heart and experimental renal diseases and vascular thickening after balloon injury. Peritoneal fibrosis is an important complication of long-term peritoneal dialysis, and peritonitis is a factor in its onset. In the present study, we investigated the effects of ANP in a rat peritonitis-induced peritoneal fibrosis model.
We investigated the role of cytokines in trimethyltin (TMT)-induced convulsive neurotoxicity. Evaluation of TNF-?, interferon-?, and interleukin (IL)-6 knockout (-/-) mice showed that the IL-6(-/-) mice had the greatest susceptibility to TMT-induced seizures. In both wild-type and IL-6(-/-) mice, TMT treatment increased glutathione oxidation, lipid peroxidation, protein oxidation, and levels of reactive oxygen species in the hippocampus. These effects were more pronounced in the IL-6(-/-) mice than in wild-type controls. In addition, the ability of TMT to induce nuclear translocation of Nrf2 and upregulation of heme oxygenase-1 and ?-glutamylcysteine ligase was significantly decreased in IL-6(-/-) mice. Treatment of IL-6(-/-) mice with recombinant IL-6 protein (rIL-6) restored these effects of TMT. Treatment with rIL-6 also significantly attenuated the TMT-induced inhibition of phosphoinositol 3-kinase (PI3K)/Akt signaling, thereby increasing phosphorylation of Bad (Bcl-xL/Bcl-2-associated death promoter protein), expression of Bcl-xL and Bcl-2, and the interaction between p-Bad and 14-3-3 protein and decreasing Bax expression and caspase-3 cleavage. Furthermore, in IL-6(-/-) mice, rIL-6 provided significant protection against TMT-induced neuronal degeneration; this effect of rIL-6 was counteracted by the PI3K inhibitor LY294002. These results suggest that activation of Nrf2-dependent glutathione homeostasis and PI3K/Akt signaling is required for the neuroprotective effects of IL-6 against TMT.
Neural cell adhesion molecule (NCAM) is a membrane protein abundantly expressed in the central nervous system. Recently, it has been reported that dysfunction of NCAM is linked to human brain disorders. Furthermore, NCAM is one of the proteolysis targets of matrix metalloproteinase (MMP), whose activation is implicated in neuronal damage. The aim of this study was to elucidate the involvement of MMP-mediated proteolysis of NCAM in the development of ischemic neuronal damage. Male ddY and MMP-9 knockout (KO) C57BL/6J mice were subjected to 2 h of middle cerebral artery occlusion (MCAO). In MCAO model mice, development of infarction and behavioral abnormality were clearly observed on days 1 and 3 after MCAO. Protein levels of MMP-2 and MMP-9 were significantly increased on days 1 and 3 after MCAO. In addition, full-length NCAM (180 kDa) was significantly decreased, but its metabolite levels increased on day 1 by ischemic stress per se. NCAM small interfering RNA significantly increased the neuronal damage induced by MCAO. MMP inhibition or MMP-9 gene KO attenuated the infarction, behavioral abnormalities, and decrease of NCAM (180 kDa) observed after MCAO in mice. The present findings clearly suggest that MMP-2/MMP-9-mediated NCAM proteolysis is implicated in the exacerbation of ischemic neuronal damage.
Interactions of environmental and genetic factors may play a role in the pathoetiology of schizophrenia. We have recently developed a novel animal model of mental disorders such as schizophrenia by inducing abnormal immune response during the perinatal period in mice with overexpression of the human dominant-negative form of disrupted-in-schizophrenia 1 (DN-DISC1). In the present study, we investigated the effects of antipsychotics on the behavioral deficits in this animal model for mental disorders with gene-environment interaction. Neonatal DN-DISC1 transgenic (DN-DISC1 tg) mice were repeatedly injected with polyriboinosinic-polyribocytidylic acid (polyI:C) for 5 days from postnatal days 2 to 6. The behavioral analyses were performed in adulthood. Clozapine (3mg/kg) or haloperidol (1mg/kg) was administered orally once a day from 1 week before starting a series of behavioral experiments and continued until the end of the study. Cognitive impairment in polyI:C-treated DN-DISC1 tg mice was improved by repeated administration of clozapine while haloperidol had no effect. Both antipsychotics suppressed the augmentation of MK-801-induced hyperactivity in the model mice. Neither clozapine nor haloperidol ameliorated the impairments of social behaviors in polyI:C-treated DN-DISC1 tg mice. These results suggest that the polyI:C-treated DN-DISC tg mice are quite unique as an animal model for mental disorders. Furthermore, this mouse model may be useful for the screening of potential antipsychotic compounds that could be more effective than clozapine in ameliorating negative symptoms and cognitive impairment in schizophrenia.
A major concern with carotid artery stenting (CAS) is the potential for cerebral embolism. The purpose of this study was to determine whether virtual histology intravascular ultrasound (VH-IVUS) can predict the risk of a silent ischemic lesion after CAS.
We describe a poorly recognised and rare complication following the endovascular embolisation of ruptured cerebral aneurysms. Three patients with dense focal subarachnoid haemorrhage (SAH) developed continuous growth of remote intracerebral haematoma (ICH) following endovascular embolisation of a ruptured aneurysm. All endovascular procedures were conducted within less than 6 hours after the onset of SAH with systemic anticoagulation and were completed uneventfully; external ventricular drainage was subsequently inserted. Repeated CT scans revealed continuous growth of ICH remote from the aneurysm without aneurysmal rebleeding. The authors suggest that endovascular embolisation for a ruptured aneurysm under systemic anticoagulation within 6 hours after SAH onset may increase the risk of expanding haematomas, especially in patients with dense focal SAH.
In Japan, biological safety cabinets (BSCs) are normally used by medical staff while handling antineoplastic agents. We have also set up a class II B2 BSC at the Division of Chemotherapy for Outpatients. The air temperature inside this BSC, however, decreases in winter. We assumed that this decrease is caused by the intake of open-air. Therefore, we investigated the effects of low open-air temperature on the BSC temperature and the time of admixtures of antineoplastic agents.
Depression has recently become a serious problem in society worldwide. However, we lack appropriate therapeutic tools, since the causes of depression remain unclear. Degeneration of neuronal cells and a decrease in neurogenesis have been suggested recently as two of the factors responsible for depression-like behavior. Furthermore, brain-derived neurotrophic factor (BDNF) is also suggested to be an important factor in recovering from such behavior. We have previously demonstrated that the hydrophobic dipeptide leucyl-isoleucine (Leu-Ile) induces BDNF in cultured neuronal cells. We therefore investigated possible antidepressant-like effects of Leu-Ile in an animal model using the repeated forced swim test (FST). Mice were forced to swim for 6 min once a day in a cylinder containing water. The mice were treated with Leu-Ile s.c. or p.o. immediately after each FST. Five-day repeated Leu-Ile treatment significantly increased BDNF mRNA levels and activated the BDNF/Akt/mTOR signaling pathway in the hippocampi of the mice. While 2-week repeated FST increased immobility time, Leu-Ile treatment for 2 weeks offset this increase. In C57BL/6J-BDNF heterozygous knockout (BDNF(+/-)) mice, Leu-Ile failed to reduce the immobility time increased by repeated FST. We next investigated the extent of cell proliferation in the hippocampus as 5-bromo-2-deoxy-uridine (BrdU) uptake into hippocampal cells. Repeated FST significantly reduced the number of BrdU-positive cells in the hippocampal dentate gyrus, while this deficit was prevented by repeated Leu-Ile treatment. These results suggest that Leu-Ile has an antidepressant-like effect, at least in part by supporting cell proliferation through the BDNF signaling pathway.
The deficits of attention result in significant impairment in daily life, and pharmacological intervention to improve attention is the most effective treatment in clinics. However, methods which are suitable for the large scale preclinical screening of attention-improving compounds or drugs are few in the field. In this study, we have developed object-based attention task as a simple and wherever-practical method that suitable for quick drug screening in mice. Treatment with p-chlorophenylalanine (pCPA) (200mg/kg/day, i.p.) for three consecutive days reduced the prefrontal cortical content of serotonin and dopamine, and increased turn-over of dopamine while decreasing turn-over of norepinephrine in the prefrontal cortex on day 7. Auditory attention and working memory, but not long-term object memory after a long (10 min) object (two objects)-exposure period, were impaired on day 7 after the same treatment paradigm with pCPA. Novel object recognition ability immediately (<10s) after a short (3 min) object (on two objects)-exposure period was not impaired after pCPA treatment. However, novel object recognition ability immediately (<10s) after a short (3 min), but not long (6 min), object (five objects)-exposure period was impaired after pCPA treatment. For the verification, the current task, the object-based attention task, was confirmed in an attention deficit model induced by acute phencyclidine (1mg/kg, i.p.) treatment in mice. It was implied that the object-based attention task would assist the behavioral screening process of pharmacological studies on attention-improving drugs.
Nicotine is hypothesized to have therapeutic effects on attentional and cognitive abnormalities in psychosis. In this study, we investigated the effect of nicotine on impaired spatial working memory in repeated methamphetamine (METH)-treated rats. Rats were administered METH (4 mg/kg, s.c.) once a day for 7 days, and their working memory was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. Control animals showed impaired performance in the test phase when the delay time was increased to 120 min or longer, while METH-treated rats showed impaired performance with a shorter delay time of 90 min. Memory impairment in METH-treated rats persisted for at least 14 days after drug withdrawal. METH-induced impairment of working memory was reversed by nicotine (0.3mg/kg, p.o., for 7 days), but the effect was diminished 7 days after the withdrawal. In control rats, nicotine decreased the number of working memory errors in the test with delay time of 120 min when administered before the training phase. Neither post-training nor pre-test administration of nicotine had any effect on working memory. These findings suggest that nicotine may have some protective effect against the impairment of working memory.
TgTauP301L mice that overexpress the mutant human tauP301L present in FTDP-17 reproduce neurofibrillary tangles (NFTs), neuronal cell losses, memory disturbance, and substantial phenotypic variation. To demonstrate factors responsible for NFT formation and neuronal cell losses, sets of TgTauP301L for comparison with or without NFTs and neuronal cell losses were studied with oligonucleotide microarrays. Gene expressions were altered in biological pathways, including oxidative stress, apoptosis, mitochondrial fatty acid betaoxidation, inflammatory response pathway, and complement and coagulation cascade pathways. Among 24 altered genes, increased levels of apolipoprotein D (ApoD) and neuronal PAS domain protein 4 (Npas4) and decreased levels of doublecortin (DCX) and potassium channel, voltage-gated, shaker-related subfamily, ? member 1 (Kcnab1) were found in the TgTauP301L with NFTs and neuronal cell losses, Alzheimers brains, and tauopathy brains. Thus, many biological pathways and novel molecules are associated with NFT formation and neuronal cell losses in tauopathy brains.
Transplantation of mesenchymal stromal cells (MSC) derived from bone marrow (BM) or adipose tissue is expected to become a cell therapy for stroke. The present study compared the therapeutic potential of adipose-derived stem cells (ASC) with that of BM-derived stem cells (BMSC) in a murine stroke model.
Since most first-generation antihistamines have undesirable sedative effects on the central nervous systems (CNS), newer (second-generation) antihistamines have been developed to improve patients quality of life. However, there are few reports that directly compare the antihistaminic efficacy and impairment of psychomotor functions. We designed a double-blind, placebo controlled, crossover study to concurrently compare the clinical effectiveness of promethazine, a first-generation antihistamine, and fexofenadine and olopatadine, second-generation antihistamines, by measuring their potency as peripheral inhibitors of histamine-induced wheal and flare. Further, we investigated their sedative effects on the CNS using a battery of psychomotor tests. When single therapeutic doses of fexofenadine (60 mg), olopatadine (5 mg) and promethazine (25 mg) were given in a double-blind manner to 24 healthy volunteers, all antihistamines produced a significant reduction in the wheal and flare responses induced by histamine. In the comparison among antihistamines, olopatadine showed a rapid inhibitory effect compared with fexofenadine and promethazine, and had a potent effect compared with promethazine. In a battery of psychomotor assessments using critical flicker fusion, choice reaction time, compensatory tracking, rapid visual information processing and a line analogue rating scale as a subjective assessment of sedation, promethazine significantly impaired psychomotor function. Fexofenadine and olopatadine had no significant effect in any of the psychomotor tests. Promethazine, fexofenadine and olopatadine did not affect behavioral activity, as measured by wrist actigraphy. These results suggest that olopatadine at a therapeutic dose has greater antihistaminergic activity than promethazine, and olopatadine and fexofenadine did not cause cognitive or psychomotor impairment.
Unstable carotid plaques are associated with an increased incidence of embolic complications after carotid artery stenting (CAS) or carotid endarterectomy (CEA). The aim of this study was to elucidate the relationship between the tissue components of carotid plaques and the incidence of new ipsilateral silent ischemic lesions (NISIL) after CAS or CEA.
Unstable carotid plaques that consist of large lipid pool and intraplaque hemorrhage are more likely to cause cerebral infarction. We previously developed an integrated backscatter (IBS) ultrasound color-coded mapping method to evaluate the tissue characteristics of plaques. The purpose of this study was to determine whether 3-dimensional IBS color-coded mapping and signal intensity ratio (SIR) from magnetic resonance imaging (MRI) could distinguish the early symptomatic plaques from late symptomatic plaques.
A 64-year-old man with chronic occlusion of common carotid artery (CCA) underwent successful recanalization with angioplasty and stenting. Patients with symptomatic CCA occlusion with hemodynamic impairment are at increased risk of subsequent stroke. Percutaneous transluminal angioplasty and stenting could be an option for chronic occluded CCA with hemodynamic impairment.
The peritoneal cavity is isolated from the outside and is usually a sterile environment. Patients on peritoneal dialysis (PD) have PD fluid (PDF) infused into the peritoneal cavity. We previously showed that unregulated complement activation could contribute to the development of peritoneal inflammation in yeast peritonitis in PD therapy. In that situation, suppression of local complement activation is essential to protect the host from further injury. The membrane complement regulators (CRegs), Crry, CD55 and CD59, are expressed in the rat peritoneum, especially along the mesothelial cell layer.
Frontotemporal craniotomy is usually necessary to perform superficial temporal artery (STA)-middle cerebral artery (MCA) double bypass for cerebrovascular occlusive disease. This report describes a less invasive technique of double bypass through a small craniotomy with minimum skin incision. Thirty-four consecutive patients underwent an elective STA-MCA double bypass via a small craniotomy from January 2006 to October 2009. The parietal and frontal branches of the STA were divided through a minimum linear or y-shaped skin incision, and these branches were anastomosed to the supra- and infrasylvian portions of the MCA. No periprocedural complication such as subdural hematoma or cutaneous necrosis occurred. Postoperative cerebral angiography within 6 months showed that the bypasses were patent in all 34 patients. Double STA-MCA bypass via a small craniotomy might be less invasive, especially for patients at high risk for postoperative hemorrhagic complication or cutaneous necrosis.
Piccolo is one of the components of the active zone at chemical synapses and regulates the transport of synaptic vesicles. The piccolo C2A domain is an important calcium sensor and binds with phosphatidylinositol or synaptotagmin-1. Recently, clinical studies suggested that a single nucleotide polymorphism in the piccolo C2A domain might be a causal risk factor for major depression. To clarify the association of piccolo with depression, we produced a transgenic mouse overexpressing the C2A domain of piccolo, and investigated the behavior of these mice. The mice exhibited depression-like behavior in both forced swim and tail suspension tests, suggesting that piccolo might regulate the depressive behavior.
Neurogenesis in the hippocampus occurs throughout life in a wide range of species and could be associated with hippocampus-dependent learning and memory. Stress is well established to seriously perturb physiological/psychological homeostasis and affect hippocampal function. In the present study, to investigate the effect of chronic restraint stress in early life on hippocampal neurogenesis and hippocampus-dependent memory, 3-week-old mice were subjected to restraint stress 6 days a week for 4 weeks. The chronic restraint stress significantly decreased the hippocampal volume by 6.3% and impaired hippocampal neurogenesis as indicated by the reduced number of Ki67-, 5-bromo-2-deoxyuridine- and doublecortin-positive cells in the dentate gyrus. The chronic restraint stress severely impaired hippocampus-dependent contextual fear memory without affecting hippocampus-independent fear memory. The expression level of brain-specific transcription factor neuronal PAS domain protein 4 (Npas4) mRNA in the hippocampus was down-regulated by the restraint stress or by acute corticosterone treatment. Npas4 immunoreactivity was detected in progenitors, immature and mature neurons of the dentate gyrus in control and stressed mice. Our findings suggest that the chronic restraint stress decreases hippocampal neurogenesis, leading to an impairment of hippocampus-dependent fear memory in mice. Corticosterone-induced down-regulation of Npas4 expression may play a role in stress-induced impairment of hippocampal function.
Parishin C, a major component of Gastrodia elata BLUME (GE), was purified from GE. Because GE modulates the serotonergic system and the 5-HT(1A) receptor is an important therapeutic target of schizophrenia, we examined whether parishin C affects phencyclidine-induced abnormal behaviors in mice. Phencyclidine-induced abnormal behaviors were significantly ameliorated by parishin C. These effects were reversed by WAY 100635, a 5HT(1A)-receptor antagonist. Consistently, parishin C showed high affinity at 5-HT(1A) receptor as well as a 5-HT(1A)-agonist activity in a 8-OH-DPAT-stimulated [(35)S]GTP-gammaS binding assay. Our results suggest that the antipsychotic effects of parishin C require activation of 5-HT(1A) receptors.
Methamphetamine is a highly addictive drug of abuse, addiction to which has increased to epidemic proportions worldwide. It has been suggested that chronic use of methamphetamine causes long-term cognitive deficits, in addition to psychiatric signs such as hallucination and delusions, which are indistinguishable from paranoid schizophrenia. Neuroimaging studies in methamphetamine abusers have demonstrated that the loss of dopamine transporters in the striatum is related to motor and cognitive impairment. In this review, we will focus on the effect of repeated treatment with methamphetamine on cognitive function in rodents. Repeated methamphetamine treatment in mice impairs long-term recognition memory after withdrawal, which is associated with the dysfunction in dopamine D1 receptor-extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in the prefrontal cortex. Methamphetamine-induced impairment of recognition memory is reversed by baclofen, clozapine, minocycline and ZSET1446. Repeated methamphetamine treatment in rats also induces impairment of spatial working memory, which is accompanied by the dysfunction of ERK1/2 pathway in the hippocampus. Repeated administration of clozapine, but not haloperidol, improves methamphetamine-induced spatial working memory impairment. These findings suggest that ERK1/2 plays an important role in memory impairments induced by repeated methamphetamine treatment. These animal models of cognitive deficits may be useful to predict the clinical effects of antipsychotics in methamphetamine psychosis and other mental disorders such as schizophrenia.
Spinal and bulbar muscular atrophy (SBMA) is a late-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract in androgen receptor (AR). Although it is commonly held that the pathogenic polyglutamine proteins accumulate in neurons and thereby induce transcriptional dysregulation, the downstream molecular events have remained elusive. Here, we examined whether TGF-beta signaling is dysregulated in SBMA. Nuclear translocation of phosphorylated Smad2/3, a key step in TGF-beta signaling, is suppressed in the spinal motor neurons of male transgenic mice carrying the mutant human AR. A similar finding was also observed in the motor neurons, but not in Purkinje cells, of SBMA patients. The pathogenic AR, the causative protein of SBMA, inhibits the transcription of TGF-beta receptor type II (TbetaRII) via abnormal interactions with NF-Y and p300/CBP-associated factor. Furthermore, overexpression of TbetaRII dampens polyglutamine-induced cytotoxicity in a neuroblastoma cell line expressing the pathogenic AR. The present study thus indicates that disruption of TGF-beta due to the transcriptional dysregulation of TbetaRII is associated with polyglutamine-induced motor neuron damage in SBMA.
Galantamine, a drug used to treat Alzheimers disease, inhibits acetylcholinesterase (AChE) and allosterically modulates nicotinic acetylcholine receptors (nAChRs) resulting in stimulation of catecholamine neurotransmission. In this study, we investigated whether galantamine exerts cognitive-improving effects through the allosteric modulation of nAChRs in an animal model of methamphetamine (Meth) psychosis. The mice treated with Meth (1 mg/kg.d) for 7 d showed memory impairment in a novel object recognition test. Galantamine (3 mg/kg) ameliorated the memory impairment, and it increased the extracellular dopamine release in the prefrontal cortex (PFC) of Meth-treated mice. Donepezil, an AChE inhibitor (1 mg/kg) increased the extracellular ACh release in the PFC, whereas it had no effect on the memory impairment in Meth-treated mice. The nAChR antagonist, mecamylamine, and dopamine D1 receptor antagonist, SCH 23390, blocked the ameliorating effect of galantamine on Meth-induced memory impairment, whereas the muscarinic AChR antagonist, scopolamine, had no effect. The effects of galantamine on extracellular dopamine release were also antagonized by mecamylamine. Galantamine attenuated the defect of the novelty-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2). The ameliorating effect of galantamine on recognition memory in Meth-treated mice was negated by microinjection of an ERK inhibitor, PD98059, into the PFC. These results suggest that the ameliorating effect of galantamine on Meth-induced memory impairment is associated with indirect activation of dopamine D1 receptor-ERK1/2 following augmentation with dopaminergic neurotransmission in the PFC through the allosteric activation of nAChRs. Galantamine could be a useful therapeutic agent for treating cognitive deficits in schizophrenia/Meth psychosis, as well as Alzheimers disease.
Methylenetetrahydrofolate reductase (MTHFR) is a critical molecule for single-carbon transfer reactions. Recent evidence suggests that polymorphisms of MTHFR are related to neural tube deficits and the pathogenesis of schizophrenia. While several studies have demonstrated associations between the gene encoding the MTHFR (MTHFR) polymorphisms and schizophrenia, these studies lack consistency. Therefore, we conducted a gene-wide association study (patients with schizophrenia = 696, control subjects = 747) and performed imputation analysis. Additionally, we performed meta-analysis on currently available data from 18 studies for two common functional polymorphisms (rs1801131 and rs1801133). There were no significant associations with schizophrenia in the single marker analysis for the seven tagging SNPs of MTHFR. In the haplotypic analysis, a nominally significant association was observed between the haplotypes, which included four SNPs (rs1801133, rs17421511, rs17037396, and rs9651118) and the schizophrenic patients. Additionally, the imputation analysis demonstrated there were several associated markers on the MTHFR chromosomal region. However, confirmatory analyses of three tagging SNPs (rs1801133, rs17037396, and rs9651118) and the top SNP (rs17421511) for the imputation results (patients with schizophrenia = 797, control subjects = 1025) failed to replicate the haplotypic analysis and the imputation results. These findings suggest that MTHFR polymorphisms are unlikely to be related to the development of schizophrenia in the Japanese population. However, since our meta-analysis results demonstrated strong support for association of rs1801133 with schizophrenia, further replication studies based on a gene-wide approach need to be considered.
In order to promote the appropriate control of cancer pain by opioids, we distributed a pocket-sized protocol pamphlet on cancer pain control and opioid prescription to the medical staff of Nagoya University Hospital. In this study, we examined whether the prescription rate of opioids for rescue use, antiemetics for preventing adverse effects, and the rate of increase of regular opioid dosage were increased after distribution to evaluate its utility. Rescue opioid prescriptions, increase of regular opioid dosage and antiemetic prescription rate after distribution were all significantly increased, compared with before distribution. Furthermore, the frequency of nausea and vomiting was reduced by the use of prophylactic antiemetics. These results suggest that distribution of this protocol for cancer pain control may contribute to appropriate pain management.
Restraining the toxic pathways of amyloid beta peptide (Abeta) by daily supplementation with dietary products has been shown effective in preventing cognitive decline. In this study, we examined the effects of the orally administered Leu-Ile, a hydrophobic dipeptide, on the neurotoxicity of Abeta(25-35) in mice. Chronic daily treatment with Leu-Ile prevented the Abeta(25-35)-induced protein nitration and impairment of novel object recognition memory in mice. Protein nitration in the hippocampus induced by Abeta(25-35) was associated with the hyperphosphorylation of extracellular signal-regulated kinase (ERK) which was found responsible for the over-expression of inducible nitric oxide synthase. Sub-chronic treatment with Leu-Ile prevented the Abeta(25-35)-induced hyperphosphorylation of ERK and protein nitration in the hippocampus. The results suggested that with the protective property against the neurotoxicity of Abeta(25-35), Leu-Ile could be considered as a candidate for the dietary supplementation in the prevention of Abeta-related impairment of recognition memory.
Ischemia of the heart, brain, and limbs is a leading cause of morbidity and mortality worldwide. Treatment with tissue type plasminogen activator (tPA) can dissolve blood clots and can ameliorate the clinical outcome in ischemic diseases. But the underlying mechanism by which tPA improves ischemic tissue regeneration is not well understood. Bone marrow (BM)-derived myeloid cells facilitate angiogenesis during tissue regeneration. Here, we report that a serpin-resistant form of tPA by activating the extracellular proteases matrix metalloproteinase-9 and plasmin expands the myeloid cell pool and mobilizes CD45(+)CD11b(+) proangiogenic, myeloid cells, a process dependent on vascular endothelial growth factor-A (VEGF-A) and Kit ligand signaling. tPA improves the incorporation of CD11b(+) cells into ischemic tissues and increases expression of neoangiogenesis-related genes, including VEGF-A. Remarkably, transplantation of BM-derived tPA-mobilized CD11b(+) cells and VEGFR-1(+) cells, but not carrier-mobilized cells or CD11b(-) cells, accelerates neovascularization and ischemic tissue regeneration. Inhibition of VEGF signaling suppresses tPA-induced neovascularization in a model of hind limb ischemia. Thus, tPA mobilizes CD11b(+) cells from the BM and increases systemic and local (cellular) VEGF-A, which can locally promote angiogenesis during ischemic recovery. tPA might be useful to induce therapeutic revascularization in the growing field of regenerative medicine.
The incidence of convulsion and associated factors were retrospectively analyzed in 23 patients with symptomatic cerebral vasospasm following subarachnoid hemorrhage (SAH) who underwent a total of 31 intra-arterial infusion of fasudil hydrochloride (IAFH) procedures in 49 vessels. Fasudil hydrochloride was administered by superselective infusion via a microcatheter positioned at the proximal portion of the affected artery. Thirteen procedures were performed by manually controlled infusion of 30-75 mg fasudil hydrochloride (1.2-3.75 mg/ml) for approximately 10 minutes. Eighteen procedures were performed by continuous infusion of 60 mg fasudil hydrochloride (1.2 mg/ml) by infusion pump at a constant rate of 3 mg/min. Neurological improvement was observed after 18 of 22 procedures in patients with neurological deterioration due to vasospasm. Convulsion during IAFH developed in 4 patients, all treated by manual infusion (p < 0.05). The manual infusion method (p < 0.05) and infusion rate greater than 3 mg/min (p < 0.01) were significantly associated with the incidence of convulsion during IAFH. IAFH was effective for treating cerebral vasospasm following aneurysmal SAH. IAFH at a constant rate of 3 mg/min delivered by infusion pump improved the symptoms of cerebral vasospasm and prevented convulsions during IAFH.
Dystrobrevin binding protein-1 gene (DTNBP1), which encodes dysbindin protein, has been identified as a schizophrenia susceptibility gene. Dysbindin has been shown to contribute to the regulation of exocytosis and formation of synaptic vesicles. Although hypofrontality in schizophrenia underlies its pathophysiology, the molecular function of dysbindin in synaptic neurotransmission remains unclear. In the present study, we investigated depolarization-evoked dopamine (DA) and serotonin (5-HT) release in the prefrontal cortex (PFC) of sandy (sdy) mice, which have a deletion mutation in the gene encoding DTNBP1. In vivo microdialysis analysis revealed that extracellular DA levels in the PFC of wild-type mice were increased by 60mM KCl stimulation, and the KCl-evoked DA release was significantly decreased in sdy mice compared with wild-type mice. Extracellular 5-HT levels in the PFC of wild-type mice were also increased by 60mM KCl stimulation. The KCl-evoked 5-HT release did not differ between wild-type and sdy mice. There was no difference in basal levels of DA and 5-HT before the stimulation between two groups. Behavioral sensitization after repeated methamphetamine (METH) treatment was significantly reduced in sdy mice compared with wild-type mice whereas no difference was observed in METH-induced hyperlocomotion between two groups. These results suggest that dysbindin may have a role in the regulation of depolarization-evoked DA release in the PFC and in the development of behavioral sensitization induced by repeated METH treatment.
Intracellular amyloid-beta peptide (Abeta) has been implicated in neuronal death associated with Alzheimers disease. Although Abeta is predominantly secreted into the extracellular space, mechanisms of Abeta transport at the level of the neuronal cell membrane remain to be fully elucidated. We demonstrate that receptor for advanced glycation end products (RAGE) contributes to transport of Abeta from the cell surface to the intracellular space. Mouse cortical neurons exposed to extracellular human Abeta subsequently showed detectable peptide intracellularly in the cytosol and mitochondria by confocal microscope and immunogold electron microscopy. Pretreatment of cultured neurons from wild-type mice with neutralizing antibody to RAGE, and neurons from RAGE knockout mice displayed decreased uptake of Abeta and protection from Abeta-mediated mitochondrial dysfunction. Abeta activated p38 MAPK, but not SAPK/JNK, and then stimulated intracellular uptake of Abeta-RAGE complex. Similar intraneuronal co-localization of Abeta and RAGE was observed in the hippocampus of transgenic mice overexpressing mutant amyloid precursor protein. These findings indicate that RAGE contributes to mechanisms involved in the translocation of Abeta from the extracellular to the intracellular space, thereby enhancing Abeta cytotoxicity.
In this study, we investigated the effects of GABA(A) and GABA(B) receptor agonists on the methamphetamine-induced impairment of recognition memory in mice. Repeated treatment with methamphetamine at a dose of 1 mg/kg for 7 days induced an impairment of recognition memory. Baclofen, a GABA(B) receptor agonist, ameliorated the repeated methamphetamine-induced cognitive impairment, although gaboxadol, a GABA(A) receptor agonist, had no significant effect. GABA(B) receptors may constitute a putative new target in treating cognitive deficits in patients suffering from schizophrenia, as well as methamphetamine psychosis.
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