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)

Elevated oxidative stress and alteration in antioxidant systems, including glutathione (GSH) decrease, are observed in schizophrenia. Genetic and functional data indicate that impaired GSH synthesis represents a susceptibility factor for the disorder. Here, we show that a genetically compromised GSH synthesis affects the morphological and functional integrity of hippocampal parvalbumin-immunoreactive (PV-IR) interneurons, known to be affected in schizophrenia. A GSH deficit causes a selective decrease of PV-IR interneurons in CA3 and dendate gyrus (DG) of the ventral but not dorsal hippocampus and a concomitant reduction of beta/gamma oscillations. Impairment of PV-IR interneurons emerges at the end of adolescence/early adulthood as oxidative stress increases or cumulates selectively in CA3 and DG of the ventral hippocampus. Such redox dysregulation alters stress and emotion-related behaviors but leaves spatial abilities intact, indicating functional disruption of the ventral but not dorsal hippocampus. Thus, a GSH deficit affects PV-IR interneuron's integrity and neuronal synchrony in a region- and time-specific manner, leading to behavioral phenotypes related to psychiatric disorders.
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PMID:Redox dysregulation affects the ventral but not dorsal hippocampus: impairment of parvalbumin neurons, gamma oscillations, and related behaviors. 2016 40

Lithium remains a mainstay in the acute and prophylactic treatment of bipolar affective disorder. It is used in the augmentation of antidepressant treatment and, less frequently, in the augmentation of antipsychotic treatment of schizophrenia. It is reported to have specific anti-suicidal effects. Thus the effect of Lithium was interesting to study on the glutathione (GSH) level in vivo conditions. Ellman's method has been used to see the effect of lithium on glutathione (GSH) level in whole blood. The time dependent effect of Lithium on the chemical status of glutathione (GSH) was determined in the whole blood (Plasma and cytosolic fraction) of human. The concentration of Glutathione was drastically decreased. The decrease in the glutathione level was concentration and time of interaction dependent, probably due to oxidation of glutathione (GSH) to corresponding disulphide (GSSG). In this paper the effect of Lithium on the Thiol/GSH level was discussed in vitro, which in principal may present a model of in vivo reaction.
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PMID:Effect of lithium metal on the chemical status of glutathione (GSH) present in whole blood (especially in plasma and cytosolic fraction in human blood). 2036 98

Accruing data suggest that oxidative stress may be a factor underlying the pathophysiology of bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Glutathione (GSH) is the major free radical scavenger in the brain. Diminished GSH levels elevate cellular vulnerability towards oxidative stress; characterized by accumulating reactive oxygen species. The aim of this study was to determine if mood disorders and SCZ are associated with abnormal GSH and its functionally related enzymes. Post-mortem prefrontal cortex from patients with BD, MDD, SCZ, and from non-psychiatric comparison controls were provided by the Stanley Foundation Neuropathology Consortium. Spectrophotometric analysis was utilized for the quantitative determination of GSH, while immunoblotting analyses were used to examine expression of glutamyl-cysteine ligase (GCL), GSH reductase (GR), and GSH peroxidase (GPx). We found that the levels of reduced, oxidized, and total GSH were significantly decreased in all psychiatric conditions compared to the control group. Although GCL and GR levels did not differ between groups, the levels of GPx were reduced in MDD and SCZ compared to control subjects. Since oxidative damage has been demonstrated in MDD, BD, and SCZ, our finding that GSH levels are reduced in post-mortem prefrontal cortex suggests that these patient groups may be more susceptible to oxidative stress.
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PMID:Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. 2063 20

Genetic studies have shown an association between schizophrenia and a GAG trinucleotide repeat (TNR) polymorphism in the catalytic subunit (GCLC) of the glutamate cysteine ligase (GCL), the key enzyme for glutathione (GSH) synthesis. The present study was aimed at analyzing the influence of a GSH dysregulation of genetic origin on plasma thiols (total cysteine, homocysteine, and cysteine-glycine) and other free amino acid levels as well as fibroblast cultures GSH levels. Plasma thiols levels were also compared between patients and controls. As compared with patients with a low-risk GCLC GAG TNR genotype, patients with a high-risk genotype, having an impaired GSH synthesis, displayed a decrease of fibroblast GSH and plasma total cysteine levels, and an increase of the oxidized form of cysteine (cystine) content. Increased levels of plasma free serine, glutamine, citrulline, and arginine were also observed in the high-risk genotype. Taken together, the high-risk genotypes were associated with a subgroup of schizophrenia characterized by altered plasma thiols and free amino acid levels that reflect a dysregulation of redox control and an increased susceptibility to oxidative stress. This altered pattern potentially contributes to the development of a biomarker profile useful for early diagnosis and monitoring the effectiveness of novel drugs targeting redox dysregulation in schizophrenia.
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PMID:Genetic dysregulation of glutathione synthesis predicts alteration of plasma thiol redox status in schizophrenia. 2067 28

As sulfur containing thiols, alpha lipoic acid (ALA) and its reduced form dihydrolipoic acid (DHLA) are powerful antioxidants and free radical scavengers capable of performing many of the same functions as glutathione (GSH). ALA supplementation may help protect mitochondria from oxidative stress, a possible mechanism contributing to certain forms of brain diseases called schizophrenia. Shortly before the advent of antipsychotic medications, two small studies found ALA relieved psychiatric symptoms in schizophrenia. More recently, animal studies have shown ALA augmentation improves mitochondrial function. At pharmaceutical levels, niacinamide helps preserve mitochondrial membrane integrity and acts as an antioxidant. ALA is a precursor for lipoamide, an essential mitochondrial coenzyme and niacinamide is a component of niacinamide adenine dinucleotide (NAD). NADH, the reduced form of NAD, is involved in the reduction of ALA to DHLA within the mitochondria. This is relevant to contemporary research because DHLA increases GSH and low GSH levels contribute to mitochondrial dysfunction and oxidative stress which have been implicated in the pathophysiology of schizophrenia.
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PMID:Is it time to reassess alpha lipoic acid and niacinamide therapy in schizophrenia? 2070 42

Accumulating evidence suggests that oxidative stress associated with impaired metabolism of the antioxidant glutathione (GSH) plays a key role in the pathophysiology of schizophrenia. Magnetic resonance spectroscopy (MRS) is one of the brain-imaging techniques that can quantitatively measure bioactive substances such as GSH in the intact human brain. Four different measurement sequences including double quantum coherence (DQC) filtering, MEscher-GArwood Point-RESolved Spectroscopy (MEGA-PRESS), Stimulated Echo Acquisition Mode (STEAM), and PRESS have been used to evaluate the (1)H-MRS measurement of GSH in the brains of patients with schizophrenia. Although the results of these studies were somewhat diverse, a negative correlation between brain GSH levels and the severity of negative symptoms in schizophrenia patients suggests that increasing the brain GSH levels might be beneficial for schizophrenia patients with negative symptoms. Moreover, a recent double-blind, placebo-controlled study demonstrated that add-on of N-acetyl-l-cysteine (NAC), a precursor of GSH, to antipsychotics improved the negative symptoms and reduced the side effects (akathisia) in patients with chronic schizophrenia. MRS study of the antioxidant defense system in schizophrenia still remains in the infantile stage; future studies are needed to examine the brain GSH level before and after NAC treatment, and thereby to provide direct evidence of the induced production of GSH in the living brain.
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PMID:Magnetic resonance spectroscopy study of the antioxidant defense system in schizophrenia. 2071

Oxidative stress has been implicated in several psychiatric illnesses, including schizophrenia. Glutathione is the brain's primary antioxidant and decreased levels of brain glutathione are reported in schizophrenia. Prepulse inhibition (PPI) is a measure of sensory gating, and PPI is reduced in schizophrenia. This study aimed to investigate the effects of brain glutathione depletion on PPI regulation. Rats and mice were treated with the glutathione-depleting agent, 2-cyclohexene-1-one (CHX), and tested for baseline PPI and its disruption by treatment with amphetamine and MK-801. Treatment with CHX caused significant depletion of GSH in frontal cortex and striatum of rats and mice. Baseline PPI and startle were not altered. However, the disruption of PPI after treatment with amphetamine was absent in CHX-treated rats. In contrast, the effect of MK-801 was not altered by CHX-treatment, nor was there any effect of CHX treatment in mice. These data show an interaction of glutathione depletion with the effects of amphetamine treatment on PPI in rats. This effect could reflect loss of plasticity in PPI regulation caused by the additive effects of CHX-induced glutathione depletion and additional oxidative stress caused by amphetamine-induced dopamine release. The significance of these results for schizophrenia is discussed.
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PMID:Interaction of glutathione depletion and psychotropic drug treatment in prepulse inhibition in rats and mice. 2081 88

Glutathione (GSH) is the primary antioxidant in the body and is present in high levels in the brain. Levels of GSH and other antioxidants are significantly altered in major psychiatric illnesses, such as schizophrenia. Recent clinical trials have demonstrated that chronic treatment with N-acetyl-l-cysteine (NAC), a GSH precursor, improved symptoms in individuals with this illness. We previously showed in rats and mice that depletion of GSH by treatment with 2-cyclohexene-1-one (CHX) induced short-term spatial memory deficits in the Y-maze test. The aim of present study was to characterise the effect of NAC in this CHX-induced glutathione depletion model. Consistent with our previous studies, CHX treatment induced approximately 50% reduction of GSH levels in striatum, hippocampus and frontal cortex tissue. GSH depletion was significantly rescued by either 1.2 g/kg or 1.6 g/kg of NAC administration, with a full recovery observed in the frontal cortex after the high dose of NAC. CHX treatment also induced a disruption in short-term spatial recognition memory in Y-maze test, as measured by the duration of time spent in the novel arm. This disruption was reversed by treatment with 1.6 g/kg of NAC. In conclusion, this study suggests that rescue of depleted levels of GSH in the brain restores cognitive deficits, as measured by the Y-maze. These effects appear to be dose-dependent and region-specific. These results may be relevant to the understanding and management of the cognitive symptoms of schizophrenia and bipolar disorder.
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PMID:Effects of N-acetyl-cysteine treatment on glutathione depletion and a short-term spatial memory deficit in 2-cyclohexene-1-one-treated rats. 2086 66

Electroconvulsive therapy (ECT) is an effective treatment alternative for schizophrenia. Previous studies have already indicated the possible effects of oxidative stress in this disorder. However, there have been no previous studies evaluating the effects of ECT on the oxidative stress in these patients. We therefore aimed to investigate the acute and chronic effects of ECT on serum levels of oxidant and antioxidant molecules in schizophrenia patients (n=28). The serum MDA and CAT levels of the patients with schizophrenia were higher than that of the controls before ECT (n=20) but there was no significant difference in the serum NO and GSH levels of the patient groups compared to the controls. We found that the NO levels of the patients were higher than the controls in the group experiencing their first episode but not in the chronic group. There was a significant clinical improvement in the patients in terms of BPRS, SANS and SAPS reduction after the 9th ECT, but not the 1st ECT. Serum MDA levels were significantly reduced compared to the baseline after the 9th ECT session although there was no significant difference after the 1st session. Separate evaluation of the patient groups revealed that the significant MDA decrease following ECT was in the patients experiencing their first episode and not in the chronic group. No significant difference was noted in the serum levels of other oxidant and antioxidant molecules after either the 1st or 9th ECT session. These results suggest that ECT does not produce any negative effect on oxidative stress in patients with schizophrenia.
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PMID:Acute and chronic effects of electroconvulsive treatment on oxidative parameters in schizophrenia patients. 2162 Sep 20

Oxidative stress and reduced brain levels of glutathione have been implicated in schizophrenia and bipolar disorder. N-acetyl cysteine (NAC) is a precursor of glutathione and has additional effects on glutamate neurotransmission, neurogenesis and inflammation. While NAC treatment has shown benefits in both schizophrenia and bipolar disorder, the mechanisms of action are largely unknown. Similarly, the interaction between oxidative stress and altered dopaminergic activities in psychiatric illness is not yet characterized. This study investigated the capacity of NAC in restoring brain glutathione depletion in rats that received 2-cyclohexene-1-one (CHX, 75 mg/kg), d-amphetamine (2.5mg/kg) or both. CHX, but not amphetamine, induced significant depletion of glutathione levels in the striatum and frontal cortex. Glutathione depletion was reversed by NAC (1000 mg/kg) in saline-treated and amphetamine-treated (frontal cortex only) rats. While NAC was shown to be beneficial in this model, the lack of additional glutathione depletion by amphetamine in combination with CHX does not support a summative interaction between oxidative stress and altered dopamine transmission.
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PMID:N-acetyl cysteine restores brain glutathione loss in combined 2-cyclohexene-1-one and d-amphetamine-treated rats: relevance to schizophrenia and bipolar disorder. 2162 86


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