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Izuru Matsumoto

Publications and source records attributed to Izuru Matsumoto.

15 recordsLinked to original sources
PubMed2006

Differential protein expression in the corpus callosum (splenium) of human alcoholics: a proteomics study.

It is widely accepted that the chronic use of alcohol induces metabolic abnormalities and neuronal damage in the brain, which can lead to cognitive dysfunction. Neuroimaging studies reveal that alcohol-induced brain damage is region specific and prominent damage has been observed in both gray and white matter of the prefrontal cortex, and a wide range of white matter structures including the corpus callosum. Molecular mechanisms underlying these structural changes are largely unknown. Using proteomics we have analysed the changes in protein expression in the splenium of the corpus callosum in two different alcoholic groups. Protein extracts from splenium of 22 human brains (nine controls, seven uncomplicated alcoholics and six complicated alcoholics with hepatic cirrhosis-designated complicated) were separated using two-dimensional gel electrophorosis. Image analysis revealed that there were significant alterations in protein expression for 25 protein spots in the uncomplicated alcoholic group and 45 in the complicated group compared to control (P<0.05; ANOVA). In a total of 72 spots (identified as 36 proteins), 15 (identified as 14 proteins) spots overlapped between two alcoholic groups. Another 32 protein spots (26 different proteins) were identified only in the complicated alcoholics. It is therefore possible that these 26 proteins in the complicated group are likely to be the results of hepatic compromise. When compared with our previous data of white matter from the prefrontal cortex in alcoholics, large numbers of identified proteins in the splenium are different. This suggests that there may be different mechanisms causing alcohol-induced brain damage in different regions of the white matter. Our data also indicate the importance of other pathways including oxidative stress, lipid peroxidation and apoptosis as potential causes of alcohol-induced brain damage.

Aged↗
PubMed2006

Effects of chronic risperidone treatment on the striatal protein profiles in rats.

Extrapyramidal symptoms (EPS) commonly occur as side effects of antipsychotic drugs (APDs) and are most likely to arise when the occupancy of dopamine D(2) receptors in the striatum by these drugs exceeds 80%. We aimed to characterize changes in the protein expression profile in the striatum of rats after chronic (4 week) supra-therapeutic (EPS-inducing) treatment with risperidone (RIS), an atypical antipsychotic drug. Administration of RIS (2.1 mg/kg/day, via subcutaneous osmotic minipumps) induced significant vacuous chewing movements and catalepsy in male Sprague-Dawley rats over a 28-day treatment period compared with a vehicle (VEH) control group (n=12) (Karl et al., unpublished observation). Using two-dimensional gel electrophoresis (2DE), total protein extracts from the rat brain striatum were separated and protein expression was analyzed by Phoretix 2D Expression and Image Beta V4.02 software followed by matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). 2DE gels resolved up to 450 protein spots, presumably different proteins and/or their isoforms. There were 30 protein spots showing statistically significant different densities between the RIS- and VEH-treated groups. All 30 proteins were successfully identified by MALDI-TOF MS, 28 of these were divided into groups based on their known functions. These included metabolic, signaling, transport, protein metabolism, chaperone, DNA binding and cell cycle categories. We conclude that chronic risperidone treatment accompanied by an EPS-like behavioral phenotype results in alterations in the striatal protein profile possibly subsequent to blockade of dopaminergic systems. These results suggest that possible mechanisms involved in APD-induced EPS include metabolic dysfunction and oxidative stress.

Analysis of Variance↗
PubMed2006

Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats.

Antipsychotic drugs have been used effectively for the treatment of schizophrenia symptoms, but they are often associated with metabolic side effects such as weight gain and endocrine disruptions. To investigate the possible mechanisms of antipsychotic-induced metabolic effects, we studied the impact of chronic administration of a typical antipsychotic drug (haloperidol) and an atypical antipsychotic (risperidone) to male rats on food intake, body weight, adiposity, and the circulating concentrations of hormones and metabolites that can influence energy homeostasis. Chronic (28days) haloperidol administration had no effect on food intake, weight gain or adiposity in male rats, whereas risperidone treatment resulted in a transient reduction in food intake and significantly reduced body weight gain compared to vehicle-treated control rats. Whereas neither antipsychotic had any effect on serum lipid profiles, glucose tolerance or the circulating concentrations of hormones controlled by the hypothalamo-pituitary-thyroid (free T4), -adrenal (corticosterone), -somatotropic (IGF-1), or -gonadotropic axes (testosterone), haloperidol increased circulating insulin levels and risperidone increased serum glucagon levels. This finding suggests that haloperidol or risperidone induce distinct metabolic effects. Since metabolic disorders such as obesity and type 2 diabetes mellitus represent serious health issues, understanding antipsychotic-induced endocrine and metabolic effects may ultimately allow better control of these side effects.

Adipose Tissue↗
PubMed2006

Protein expression profile in the striatum of acute methamphetamine-treated rats.

PURPOSE: Methamphetamine (MAP) is an addictive drug with psychostimulant effects. It is known that MAP induces behavioral changes, including hyperlocomotion and stereotypical movements in rodents. These behavioral changes induced by MAP have been compared with behavioral changes in patients with MAP addiction and MAP psychosis. However, little is known about the underlying mechanisms of MAPs effects on global protein expression. 2-DE proteomics allows us to examine global changes in protein expression in complex biological systems and to propose possible hypotheses of the underlying mechanisms in various pathological conditions. In the present study, we aim to identify protein expression profiles in the striatum (ST) of acute low dose MAP (1 mg/kg)-treated rats using 2-DE proteomics. MATERIALS AND METHODS: Rats were given an intraperitoneal injection of MAP (1 mg/kg) or saline. Locomotor activity was monitored. Proteins were extracted from the ST of MAP-treated and saline-treated control rats then separated and analyzed using 2-DE. RESULTS. Low dose MAP administration significantly increased locomotor activity. 2-DE analysis revealed 36 protein spots differentially regulated in the ST of acute MAP-treated rats compared to a vehicle-treated control. 26 protein spots have been identified using MALDI-TOF, including phosphoglycerate kinase 1, Dihydrolipoamide dehydrogenase, Voltage-dependent anion-selective channel protein 1, Rho GDP dissociation inhibitor alpha, peroxiredoxin 2, ubiquitin carboxy-terminal hydrolase L1, and actin beta, N-tropomodulin. DISCUSSION: These proteins could be related to underlying mechanisms of acute low dose MAP effects, indicating mitochondrial dysfunction, oxidative damages, lysosomal degradation, degenerative processes, and neuronal modification.

Animals↗
PubMed2006

Behavioural effects of chronic haloperidol and risperidone treatment in rats.

The therapeutic properties of typical antipsychotic drugs (APDs) such as haloperidol in schizophrenia treatment are mainly associated with their ability to block dopamine D2 receptors. This blockade is accompanied by side effects such as extrapyramidal symptoms (EPS). Atypical APDs such as risperidone have superior therapeutic efficacy possibly due to their activity at multiple receptors (in particular 5-HT2A receptors). Although the risk of EPS is significantly lower in atypical than in typical APDs, it is not negligible. To investigate and compare the behavioural profile and EPS-asssociated side effects of haloperidol and risperidone APD treatment we applied a multi-tiered, comprehensive behavioural phenotyping approach. Sprague-Dawley rats were treated chronically (28 days) with supratherapeutic EPS-inducing doses of haloperidol and risperidone using osmotic minipumps. Domains such as motor activity, exploration, memory, and anxiety were analysed together with EPS assessment ("early onset" vacuous chewing movements and catalepsy). Both APDs produced diminished motor activity and exploration, impaired working memory performances, and increased anxiety levels. These effects were more pronounced in haloperidol-treated animals. Chronic APD treatment also caused a time-course dependent elevation of EPS-like symptoms. Risperidone-treated animals showed a catalepsy-like phenotype, which differed to that of haloperidol-treated rats, indicating that processes other than the anticipated dopaminergic mechanisms are underlying this phenomenon. These EPS-related phenotypes are consistent with reported EPS-inducing D2 receptor occupancies of around 80%. Differences in the behavioural profile of haloperidol and risperidone, which were revealed by a comprehensive phenotyping strategy, are likely due to the unique receptor activation profiles of these APDs.

Animals↗
PubMed2006

Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder: relevance to neuronal network perturbation.

The limited number of genome-wide transcriptome analyses using the postmortem brains of bipolar disorder sufferers has not produced a clear consensus on the molecular pathways affected by the disorder. To expand the knowledge in this area, we examined the expression levels of more than 12 000 genes in Brodmann's Area (BA), 46 (dorsolateral prefrontal cortex) from bipolar I disorder and control samples using Affymetrix GeneChips. This analysis detected 108 differentially expressed genes in bipolar brains. Validation studies using quantitative RT-PCR on the two original diagnostic cohorts plus tissue from schizophrenic subjects, confirmed the differential expressions of eight genes (RAP1GA1, SST, HLA-DRA, KATNB1, PURA, NDUFV2, STAR and PAFAH1B3) in a bipolar-specific manner and one gene (CCL3) which was downregulated in both bipolar and schizophrenic brains. Of these, protein levels of RAP1GA1 (RAP1 GTPase activating protein 1) showed a trend of increase in BA46 from bipolar brains, in keeping with mRNA transcript levels. Transmission disequilibrium analysis of the nine genes using 43 single nucleotide polymorphisms (SNPs) in 229 National Institute of Mental Health bipolar trios exposed nominal SNP association and modest empirical haplotypic association (P=0.033) between SST (somatostatin) and disease. Finally, gene network analysis using the currently obtained expression data highlighted cellular growth and nervous system development pathways as potential targets in the molecular pathophysiology of bipolar disorder.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2006

Failure to support a genetic contribution of AKT1 polymorphisms and altered AKT signaling in schizophrenia.

The protein kinase v-akt murine thymoma viral oncogene homolog (AKT) gene family comprises three human homologs that phosphorylate and inactivate glycogen synthase kinase 3beta (GSK3beta). Studies have reported the genetic association of AKT1 with schizophrenia. Additionally, decreased AKT1 protein expression and the reduced phosphorylation of GSK3beta were reported in this disease, leading to a new theory of attenuated AKT1-GSK3beta signaling in schizophrenia pathogenesis. We have evaluated this theory by performing both genetic and protein expression analyses. A family based association test of AKT1 did not show association with schizophrenia in Japanese subjects. The expression levels of total AKT, AKT1 and phosphorylated GSK3beta detected in the schizophrenic brains from two different brain banks also failed to support the theory. In addition, no attenuated AKT-GSK3beta signaling was observed in the lymphocytes from Japanese schizophrenics, contrasting with previous findings. Importantly, we found that the level of phosphorylated GSK3beta at Ser9 tended to be inversely correlated with postmortem intervals, and that the phosphorylation levels of AKT were inversely correlated with brain pH, issues not assessed in the previous study. These data introduce a note of caution when estimating the phosphorylation levels of GSK3beta and AKT in postmortem brains. Collectively, this study failed to support reduced signaling of the AKT-GSK3beta molecular cascade in schizophrenia.

Female↗
PubMed2005

Expression of human neuronal protein 22, a novel cytoskeleton-associated protein, was decreased in the anterior cingulate cortex of schizophrenia.

Human neuronal protein 22 (hNP22) is a novel neuron-specific protein featuring numerous motifs previously described in cytoskeleton-associating and signaling proteins. Because previous studies have supported abnormalities in neuronal cytoarchitecture and/or development in the schizophrenia brain, we examined the expression of hNP22 in the anterior cingulate cortex, the hippocampus and the prefrontal cortex of schizophrenic and normal control postmortem brains using high-sensitive immunohistochemistry. Seven schizophrenic and seven age- and sex-matched control brains were examined. The ratio of hNP22-immunopositive cells/total cells was significantly reduced in layer V (p=.020) and layer VI (p=.022) of the anterior cingulate cortex of schizophrenic brain compared with controls. In contrast, there were no significant changes observed in the hippocampus and the prefrontal cortex. These results suggest that altered expression of hNP22 may be associated with modifications in neuronal cytoarchitecture leading to dysregulation of neural signal transduction in the anterior cingulate cortex of the schizophrenia brain.

Actins↗
PubMed2005

5-HT2A and muscarinic receptors in schizophrenia: a postmortem study.

Although evidence suggests that 5-HT(2A) and muscarinic M1/M4 receptors are implicated in the pathology of schizophrenia, the results are not conclusive. In the present study we tested the hypothesis that binding of 5-HT(2A) and M1/M4 receptors is altered in the postmortem brain of schizophrenia subjects. Quantitative autoradiography was employed to measure [(3)H]ketanserin binding to 5-HT(2A) receptors and [(3)H]pirenzepine binding to both M1 and M4 receptors in Brodmann's area 9 (BA9), caudate/putamen, and the hippocampal formation from six schizophrenic and six control subjects. A significant reduction in the density of 5HT(2A) receptors in BA 9 of schizophrenic subjects was observed (p=0.036). No significant difference was observed in the density of 5HT(2A) receptors in the hippocampus or caudate/putamen between the two groups. No significant changes in the density of M1/M4 receptors was observed in these three regions between the two groups. These findings support a possible involvement of the serotonergic system in the pathology of schizophrenia.

Aged↗
PubMed2005

Ethanol and brain damage.

It is now well established that even uncomplicated alcoholics who have no specific neurological or hepatic problems show signs of regional brain damage and cognitive dysfunction. Improvements in neuroimaging technology, magnetic resonance imaging, magnetic resonance spectroscopy and positron emission tomography have contributed significantly, revealing alcoholic-specific changes in the CNS associated with neuropsychological abnormalities. Although greater efforts are needed, a human brain bank specifically targeting alcohol cases is now able to provide fresh and frozen tissue for alcohol researchers. These tissues can be used to test hypotheses developed using animal models and/or in vitro studies. The aim is to delineate mechanisms underlying alcohol-related brain damage in humans. The development of high-throughput, non-hypothesis-driven approaches using DNA microarrays and proteomics might also provide clues to this important problem.

Aged↗
PubMed2005

Alcohol-responsive genes in the frontal cortex and nucleus accumbens of human alcoholics.

The molecular processes underlying alcohol dependence are not fully understood. Many characteristic behaviours result from neuroadaptations in the mesocorticolimbic system. In addition, alcoholism is associated with a distinct neuropathology. To elucidate the molecular basis of these features, we compared the RNA expression profile of the nucleus accumbens and prefrontal cortex of human brain from matched individual alcoholic and control cases using cDNA microarrays. Approximately 6% of genes with a marked alcohol response were common to the two brain regions. Alcohol-responsive genes were grouped into 11 functional categories. Predominant alcohol-responsive genes in the prefrontal cortex were those encoding DNA-binding proteins including transcription factors and repair proteins. There was also a down-regulation of genes encoding mitochondrial proteins, which could result in disrupted mitochondrial function and energy production leading to oxidative stress. Other alcohol-responsive genes in the prefrontal cortex were associated with neuroprotection/apoptosis. In contrast, in the nucleus accumbens, alcohol-responsive genes were associated with vesicle formation and regulation of cell architecture, which suggests a neuroadaptation to chronic alcohol exposure at the level of synaptic structure and function. Our data are in keeping with the previously reported alcoholism-related pathology characteristic of the prefrontal cortex, but suggest a persistent decrease in neurotransmission and changes in plasticity in the nucleus accumbens of the alcoholic.

Adult↗
PubMed2004

Selective reduction of chromogranin A-like immunoreactivities in the prefrontal cortex of schizophrenic subjects: a postmortem study.

It is suggested that secretogranins/chromogranins play a role in regulating secretion of various proteins and amines, including neurotransmitters from secretory granules. Several studies have implicated the importance of altered synaptic connectivity in schizophrenia. We employed immunohistochemical techniques to determine if the level of chromogranin A (CgA)-immunoreactivity (IR) was altered in the subjects with schizophrenia. Nine subjects with schizophrenia and nine age- and sex-matched control subjects were selected for this study. Immunohistochemistry using specific antibody against CgA was performed on sections of prefrontal cortex and hippocampus. Images of CgA-IR were analyzed by computer-based image analyzing software. CgA-IR was significantly decreased in layers III-V of the prefrontal cortex in schizophrenic subjects compared with control subjects. In the hippocampus, no significant difference was observed between two groups. The results indicate that there may be a decrease in the number of CgA positive large dense-core vesicles per terminal, and/or in the number of CgA positive terminals, suggesting possible functional impairment of prefrontal synaptic contact in schizophrenia.

Adolescent↗
PubMed2003

How important are brain banks for alcohol research?

This article contains the proceedings of a symposium at the 2002 RSA/ISBRA Meeting in San Francisco, organized and chaired by Clive Harper and co-chaired by Izuru Matsumoto. The presentations were (1) Introduction, by Clive Harper; (2) The quality of tissue-a critical issue, by Therese Garrick; (3) The first systematic brain tissue donor program in Japan, by Izuru Matsumoto; (4) Brain scans after death-really! by Adolf Pfefferbaum, Elfar Adalsteinsson, and Edith Sullivan; (5) Capture that (genial) expression, by Joanne Lewohl and Peter Dodd; and (6) Neurochemical/pharmacological studies: experimental design and limitations, by Roger Butterworth.

Alcohol-Induced Disorders, Nervous System↗
PubMed2003

Expression of hNP22 is altered in the frontal cortex and hippocampus of the alcoholic human brain.

BACKGROUND: Human neuronal protein (hNP22) is a gene with elevated messenger RNA expression in the prefrontal cortex of the human alcoholic brain. hNP22 has high homology with a rat protein (rNP22). These proteins also share homology with a number of cytoskeleton-interacting proteins. METHODS: A rabbit polyclonal antibody to an 18-amino acid epitope was produced for use in Western and immunohistochemical analysis. Samples from the human frontal and motor cortices were used for Western blots (n = 10), whereas a different group of frontal cortex and hippocampal samples were obtained for immunohistochemistry (n = 12). RESULTS: The hNP22 antibody detected a single protein in both rat and human brain. Western blots revealed a significant increase in hNP22 protein levels in the frontal cortex but not the motor cortex of alcoholic cases. Immunohistochemical studies confirmed the increased hNP22 protein expression in all cortical layers. This is consistent with results previously obtained using Northern analysis. Immunohistochemical analysis also revealed a significant increase of hNP22 immunoreactivity in the CA3 and CA4 but not other regions of the hippocampus. CONCLUSIONS: It is possible that this protein may play a role in the morphological or plastic changes observed after chronic alcohol exposure and withdrawal, either as a cytoskeleton-interacting protein or as a signaling molecule.

Adult↗