Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clozapine, an atypical antipsychotic drug effective in treatment of refractory schizophrenia causes potentially life-threatening agranulocytosis. The drug undergoes bioactivation to a toxic, chemically reactive intermediate with capacity to target stromal cells, central components of the bone marrow microenvironment implicated in neutrophil development. To identify possible mechanisms underpinning disruption of stroma as a site of drug bioactivation, toxicity was induced in vitro. Therefore metabolite generation procedures utilizing HOCl or HRP-H(2)O(2) as primary components involved in clozapine metabolism were adapted for stromal culture and coupled with viability determinations. Drug oxidation by HOCl was less toxic to stromal cells than HRP-H(2)O(2) based methods. More specifically, clozapine bioactivation by HRP-H(2)O(2) caused dose-dependent inhibition of stromal viability at therapeutically relevant concentrations. Differences in susceptibility of HAS303 and LP101 cells to the clozapine nitrenium ion were also evident. Stromal cell death was attributed to clozapine in the presence of a complete metabolising system comprising HRP and H(2)O(2). In the absence of a complete metabolising system clozapine was not cytotoxic. For LP101 cells, drug plus HRP (minus H(2)O(2)) also induced toxicity. Importantly, other antipsychotic drugs including risperidone, olanzapine and haloperidol when bioactivated, were not cytotoxic, indicating system specificity for clozapine. Exogenous GSH, N-acetylcysteine, l-ascorbic acid, catalase, and sodium azide afforded protection to cells whereas S-methylGSH, GSSG, ketoprofen and proadifen did not. Thus functional data derived from the in vitro stromal system defined in these studies may enable further investigation of the mechanisms subserving stromal impairment in clozapine-induced agranulocytosis and direct attention to improved methods for its prevention.
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PMID:Clozapine bioactivation induces dose-dependent, drug-specific toxicity of human bone marrow stromal cells: a potential in vitro system for the study of agranulocytosis. 1684 94

Oxidative stress could be involved in the pathophysiology of schizophrenia, a major psychiatric disorder. Glutathione (GSH), a redox regulator, is decreased in patients' cerebrospinal fluid and prefrontal cortex. The gene of the key GSH-synthesizing enzyme, glutamate cysteine ligase modifier (GCLM) subunit, is strongly associated with schizophrenia in two case-control studies and in one family study. GCLM gene expression is decreased in patients' fibroblasts. Thus, GSH metabolism dysfunction is proposed as one of the vulnerability factors for schizophrenia.
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PMID:Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene. 1690 99

The aims of this study are to investigate the contribution effect of oxidative stress in MK-801-induced experimental psychosis model, and to show that prevention of oxidative stress may improve prognosis. Because oxidative damage has been suggested in the neuropathophysiology of schizophrenia, the possible protecting agents against lipid peroxidation are potential target for the studies in this field. For this purpose, Wistar Albino rats were divided into three groups: the first group was used as control, MK-801 was given to the rats in the second group and MK-801+omega-3 essential fatty acids (EFA) was given to the third group. MK-801 was given intraperitoneally at the dose of 0.5mg/(kgday) once a day for 5 days in experimental psychosis group. In the second group, 0.8g/(kgday), omega-3 FA (eicosapentaenoic acid, 18%, docosahexaenoic acid, 12%) was given to the rats while exposed MK-801. In control group, saline was given intraperitoneally at the same time. After 7 days, rats were killed by decapitation. Prefrontal brain area was removed for histological and biochemical analyses. As a result, malondialdehyde (MDA), as an indicator of lipid peroxidation, protein carbonyl (PC), as an indicator of protein oxidation, nitric oxide (NO) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities as antioxidant enzymes, and xanthine oxidase (XO) and adenosine deaminase (AD) activities as an indicator of DNA oxidation was found to be increased significantly in prefrontal cortex (PFC) of MK-801 group (P<0.0001) compared to control group. In omega-3 FA treated rats, prefrontal tissue MDA, PC and NO levels as well as SOD, GSH-Px, XO, and AD enzyme activities were significantly decreased when compared to MK-801 groups (P<0.0001) whereas catalase (CAT) enzyme activity was not changed. Moreover, in the light of microscopic examination of MK-801 groups, a great number of apoptotic cells were observed. omega-3 FA supplementation decreased the apoptotic cell count in PFC. The results of this study revealed that oxidative stress and apoptotic changes in PFC may play an important role in the pathogenesis of MK-801-induced neuronal toxicity. This experimental study also provides some evidences for the protective effects of omega-3 FA on MK-801-induced changes in PFC of rats.
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PMID:The protective effects of omega-3 fatty acids against MK-801-induced neurotoxicity in prefrontal cortex of rat. 1697 Oct 21

The high rate of smoking in schizophrenia may reflect patients' attempts to reduce the side effects of antipsychotic medications, and one mechanism for this reduction may be a reduction in oxidative stress and free radical-mediated brain damage that may contribute to schizophrenic symptoms and to complications of its treatment. Symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS), side effects were assessed with the Simpson and Angus Rating Scale (SAS), and malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were measured in plasma. All of these measures were compared in 130 male inpatients with DSM-IV schizophrenia: 104 smokers and 26 non-smokers. The results showed that the positive PANSS symptoms were lower in smokers than non-smokers (14.5 vs 17.5), while the negative symptoms were lower in those who smoked more cigarettes (r=-0.23). The SAS showed no differences. The CAT activity was correlated with both GSH-Px and SOD activities. Of the three enzymes only the CAT activity was significantly higher in smokers than non-smokers (2.9 vs 1.6 U/ml), but greater SOD activity correlated more cigarettes smoked (r=0.24). Consistent with some protection against oxidative stress, MDA also was significantly lower in smokers than non-smokers (9.2 vs 14.4 nmol/ml). The fewer positive symptoms in smokers and fewer negative symptoms in those who smoked more cigarettes may be a selection bias, but appears to be associated with decreased oxidative stress and lipid peroxidation in schizophrenics who smoke tobacco.
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PMID:Nicotine dependence, symptoms and oxidative stress in male patients with schizophrenia. 1722 36

MK-801 was shown to be one of the most neurotoxic non-competitive NMDA receptor antagonists. It is known that repeated injection of MK-801 was proposed in an animal model in psychosis. The aims of this study are to investigate the contributing effect of oxidative stress in MK-801-induced experimental psychosis model, and to show that prevention of oxidative stress may improve prognosis. Furthermore, there is evidence that oxygen free radicals play an important role in the pathophysiology of schizophrenia. In this study, Wistar Albino rats were divided into three groups: 1st group: Control, 2nd group: MK-801, 3rd group: MK-801+CAPE (Caffeic acid phenethyl ester) group. MK-801 was given intraperitoneally at the dose of 0.5 mg/kg/day for 5 days. CAPE was given to the treatment group while exposed to MK-801. In control group, saline was given intraperitoneally at the same time. After 7 days, rats were killed by decapitation. Prefrontal cortex (PFC) of rats was removed for biochemical and histological analyses. As a result, malondialdehyde (MDA), protein carbonyl (PC), nitric oxide (NO) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and xanthine oxidase (XO) and adenosine deaminase (AD) enzyme activities were found to be increased significantly in prefrontal cortex (PFC) of MK-801 group (p<0.0001) compared to control group. In CAPE treated rats, prefrontal tissue MDA, PC, NO levels and, GSH-Px, XO, AD enzyme activities were significantly decreased when compared to MK-801 groups (p<0.0001) whereas catalase (CAT) enzyme activity was not changed. Moreover, in the light of microscopic examination of MK-801 groups, a great number of apoptotic cells were observed. CAPE treatment decreased the apoptotic cell count in PFC. The results of this study showed that MK-801-induced neurotoxicity caused oxidative stress in PFC of rats. This experimental study may also provide some evidences for the new treatment strategies with antioxidants in schizophrenia.
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PMID:Oxidative stress in prefrontal cortex of rat exposed to MK-801 and protective effects of CAPE. 1737 54

Glutathione (GSH) metabolism dysfunction is one risk factor in schizophrenia. A transitory brain GSH deficit was induced in Wistar (WIS) and mutant (ODS; lacking ascorbic acid synthesis) rats using BSO (l-buthionine-(S,R)-sulfoximine) from post-natal days 5-16. When GSH was re-established to physiological levels, juvenile BSO-ODS rats were impaired in the water maze task. Long after treatment cessation, adult BSO-WIS/-ODS rats showed impaired place discrimination in the homing board with distributed visual or olfactory cues. Their accuracy was restored when a single cue marked the trained position. Similarly, more working memory errors were made by adult BSO-WIS in the radial maze when several olfactory cues were present. These results reveal that BSO rats did not suffer simple sensory impairment. They were selectively impaired in spatial memory when the task required the integration of multimodal or olfactory cues. These results, in part, resemble some of the reported olfactory discrimination and cognitive impairment in schizophrenia.
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PMID:Transitory glutathione deficit during brain development induces cognitive impairment in juvenile and adult rats: relevance to schizophrenia. 1745 16

Schizophrenia is a complex multifactorial brain disorder with a genetic component. Convergent evidence has implicated oxidative stress and glutathione (GSH) deficits in the pathogenesis of this disease. The aim of the present study was to test whether schizophrenia is associated with a deficit of GSH synthesis. Cultured skin fibroblasts from schizophrenia patients and control subjects were challenged with oxidative stress, and parameters of the rate-limiting enzyme for the GSH synthesis, the glutamate cysteine ligase (GCL), were measured. Stressed cells of patients had a 26% (P = 0.002) decreased GCL activity as compared with controls. This reduction correlated with a 29% (P < 0.001) decreased protein expression of the catalytic GCL subunit (GCLC). Genetic analysis of a trinucleotide repeat (TNR) polymorphism in the GCLC gene showed a significant association with schizophrenia in two independent case-control studies. The most common TNR genotype 7/7 was more frequent in controls [odds ratio (OR) = 0.6, P = 0.003], whereas the rarest TNR genotype 8/8 was three times more frequent in patients (OR = 3.0, P = 0.007). Moreover, subjects with disease-associated genotypes had lower GCLC protein expression (P = 0.017), GCL activity (P = 0.037), and GSH contents (P = 0.004) than subjects with genotypes that were more frequent in controls. Taken together, the study provides genetic and functional evidence that an impaired capacity to synthesize GSH under conditions of oxidative stress is a vulnerability factor for schizophrenia.
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PMID:Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. 1792 Dec 51

Several lines of evidence suggest that oxidative stress plays a role in the pathogenesis of schizophrenia, and that glutathione (GSH) plays a crucial role in antioxidant defense mechanisms. In this study, we performed association studies between GSH-related genes (GSTM1, GSTP1, GSTO1, GSTT1, GSTT2, GPX1, and GCLM) and schizophrenia in a Japanese population. The overall distributions of the genotypes and alleles of each gene were not different between schizophrenic patients and controls. Subjects with residual-type schizophrenia showed different distributions in the analysis of GSTM1 genotype and in the combination analysis of GSTs, GPX1, and GCLM genotypes although the small sample size should be considered as a limitation of this study. In addition, our findings revealed that there were large ethnic differences in the genotype distributions of those GSH-related genes. The present study suggests that GSH-related genes may not play a major role in the pathogenesis of schizophrenia in a Japanese population. However, a dysregulation of GSH metabolism may be one of the vulnerability factors contributing to the development of a certain type of schizophrenia, and it is likely that the ethnic background should be considered in further study for those GSH-related genes.
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PMID:Association study between the genetic polymorphisms of glutathione-related enzymes and schizophrenia in a Japanese population. 1844 62

The role of brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology as well as treatment outcome of schizophrenia. Rodent studies indicate that several antipsychotic drugs have time-dependent (and differential) effects on BDNF levels in the brain. Earlier studies from our laboratory have indicated that long-term treatment with haloperidol (HAL) decreases BDNF, reduced GSH and anti-apoptotic marker, Bcl-xl protein levels and increases the expression of pro-apoptotic proteins in rat frontal cortex. Furthermore, findings from human as well as rodent studies suggest that treatment of schizophrenia must involve the neuroprotective strategies to improve the neuropathology and thereby clinical outcome. In the present study, we investigated the potential of cystamine (CYS), an anti-oxidant and anti-apoptotic compound, to prevent HAL-induced reduction in BDNF, GSH, and Bcl-xl protein levels in mice and the signaling mechanism(s) involved in the beneficial effects of CYS. The results indicated that CYS as well as cysteamine (the FDA-approved precursor of CYS) increased BDNF protein levels in mouse frontal cortex 7 days after treatment. CYS co-treatment prevented chronic HAL treatment-induced reduction in BDNF, GSH, and Bcl-xl protein levels. CYS treatment enhanced TrkB-tyrosine phosphorylation and activated Akt and extracellular signal-regulated kinase (ERK)1/2, downstream molecules of TrkB signaling. In addition, in vitro experiments with mouse cortical neurons showed that CYS prevented the HAL-induced reduction in neuronal cell viability and BDNF protein levels, and increase in apoptosis. BDNF-neutralizing antibody as well as K252a, a selective inhibitor of neurotrophin signaling blocked the CYS-mediated neuroprotection. Moreover, CYS-mediated neuroprotection is also blocked by LY294002, a phosphatidylinositol 3-kinase inhibitor or PD98059, a mitogen-activated protein kinase kinase (MEK) inhibitor. Thus, CYS protects cortical neurons through a mechanism involving TrkB receptor activation, and a signaling pathway involving phosphatidylinositol 3-kinase and MAPK. The findings from the present study may be helpful for the development of novel neuroprotective strategies to improve the treatment outcome of schizophrenia.
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PMID:Cystamine prevents haloperidol-induced decrease of BDNF/TrkB signaling in mouse frontal cortex. 1878 74

An impaired glutathione (GSH) synthesis was observed in several multifactorial diseases, including schizophrenia and myocardial infarction. Genetic studies revealed an association between schizophrenia and a GAG trinucleotide repeat (TNR) polymorphism in the catalytic subunit (GCLC) of the glutamate cysteine ligase (GCL). Disease-associated genotypes of this polymorphism correlated with a decrease in GCLC protein expression, GCL activity and GSH content. To clarify consequences of a decreased GCL activity at the proteome level, three schizophrenia patients and three controls have been selected based on the GCLC GAG TNR polymorphism. Fibroblast cultures were obtained by skin biopsy and were challenged with tert-butylhydroquinone (t-BHQ), a substance known to induce oxidative stress. Proteome changes were analyzed by two dimensional gel electrophoresis (2-DE) and results revealed 10 spots that were upregulated in patients following t-BHQ treatment, but not in controls. Nine corresponding proteins could be identified by MALDI mass spectrometry and these proteins are involved in various cellular functions, including energy metabolism, oxidative stress response, and cytoskeletal reorganization. In conclusion, skin fibroblasts of subjects with an impaired GSH synthesis showed an altered proteome reaction in response to oxidative stress. Furthermore, the study corroborates the use of fibroblasts as an additional mean to study vulnerability factors of psychiatric diseases.
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PMID:Skin fibroblast model to study an impaired glutathione synthesis: consequences of a genetic polymorphism on the proteome. 1904 95


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