Antioxidant enzymes and lipid peroxidation in different forms of schizophrenia treated with typical and atypical antipsychotics

There is accumulating evidence of altered antioxidant enzyme activities and increased levels of lipid peroxidation in schizophrenia. Free radical-mediated abnormalities may contribute to specific aspects of schizophrenic symptomatology and complications of its treatment. However, few studies have evaluated both antioxidant enzymes and lipid peroxidation in the same schizophrenic patient groups treated with typical or atypical antipsychotics. Plasma malondialdehyde (MDA) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were analyzed using established procedures in 92 medicated schizophrenia including paranoid (n=34), disorganized (n=18) and residual subtypes (n=40), as well as in control subjects (n=50). The results showed that activities of SOD and GSH-Px were decreased but levels of MDA were elevated in patients with a chronic form of schizophrenia as compared with normal controls. SOD and GSH-Px activities were found to be significantly lower in paranoid and residual subtypes compared to both disorganized subtype and the control group. MDA levels were significantly higher in all subtypes compared to the control group. There were no significant differences in any parameters measured among all three subgroups treated with clozapine (n=44), risperidone (n=20) and typical antipsychotics (n=28). Additionally, a significantly higher MDA levels, but a significantly lower CAT activity was noted in female than male patients. These results suggest that oxidative stress may be implicated in the pathophysiology of all subtypes of schizophrenia, which may contribute to the increased membrane lipid peroxidation. Long-term treatments with typical and atypical antipsychotics may produce the similar effects on the antioxidant enzymes and lipid peroxidation.     

The correlation between early alcohol withdrawal severity and oxidative stress in patients with alcohol dependence

Oxidative stress is enhanced in alcoholic patients. This clinical study aimed to explore the correlation between alcohol withdrawal severity and two oxidative stress markers, malondialdehyde (MDA) and superoxide dismutase (SOD). Seventy-six inpatients fulfilled the DSM-IV-TR criteria for alcohol dependence and 19 healthy controls were enrolled. Serum MDA level and SOD activity were measured within 24 h of alcohol detoxification. The severity of alcohol withdrawal was evaluated by the Chinese version of the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar-C) every 8 h. Average and highest scores of the CIWA-Ar-C at the first day were recorded as the baseline withdrawal severity. We compared the differences of MDA and SOD between groups, and examined the correlation between baseline withdrawal severity and oxidative stress markers. Compared to controls, serum MDA levels were significantly elevated and SOD activity was significantly lowered in alcoholic patients. In stepwise multiple regression analysis, MDA was the only variable significantly correlated with the average (beta=0.48, p<0.0001) and highest (beta=0.47, p<0.0001) CIWA-Ar-C scores at the first day of detoxification. In agreement with previous studies, alcoholic patients encountered high oxidative stress. Although there was a correlation between early withdrawal severity and MDA levels, the meanings of the correlation are worth further studies in the future.     

The reduction of superoxide dismutase activity is associated with the severity of neurological soft signs in patients with schizophrenia

This study aimed to explore the relationship between antioxidant enzyme activities and neurological soft signs (NSS) in a sample of patients with schizophrenia. Sixty clinically stable patients with schizophrenia treated mostly by first-generation antipsychotics and 30 matched healthy controls were recruited. NSS were assessed in two groups by a standardized neurological examination (Krebs et al., 2000). The red blood cell (RBC) antioxidant activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were measured by spectrophotometry. RBC activities of all enzymes studied: SOD, GSH-Px and CAT, were significantly lower in the patients compared to control group. All NSS scores were significantly higher in the patients compared to healthy controls' scores. In the patients, a negative correlation was found between RBC SOD activity and NSS total score and motor coordination and motor integration sub-scores. The association between low SOD activity as a marker of oxidative stress and NSS in schizophrenic patients suggests a common pathological process of these abnormalities.     

Changes in oxidative stress markers in patients with schizophrenia: The effect of antipsychotic drugs

The aim of this study was to investigate the serum levels or activities of oxidative stress markers in patients with schizophrenia in acute phase and evaluate the changes in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH) and thiobarbituric acid-reactive substances (TBARS) after treatment. We consecutively enrolled 41 patients with schizophrenia in acute phase, and 27 patients were followed up with a 4-week antipsychotic treatment. Serum oxidative stress markers were measured with assay kits. We found that Positive and Negative Syndrome Scale (PANSS) total scores were significantly negatively correlated with serum GPx activity and GSH levels and positively correlated with serum SOD activity in patients with schizophrenia in acute phase. In addition, serum GPx activity had a positive correlation with GSH levels and negative correlation with SOD activity. We also found that serum SOD activity was significantly negatively correlated with TBARS levels in patients in acute phase. Furthermore, we found significantly increased changes only in GPx activity in female patients receiving the 4-week treatment (P=0.006). In conclusion, our results suggest that SOD, GPX and GSH might be indicators of schizophrenia severity in acute phase. Furthermore, antipsychotic drugs might affect serum GPx activity in female patients receiving the 4-week treatment.     

Oxidative-antioxidative systems and their relation with serum S100 B levels in patients with schizophrenia: effects of short term antipsychotic treatment

Oxidative stress may be a contributing factor in the etiopathophysiology of schizophrenia, which may be exacerbated by the treatment with antipsychotics with pro-oxidant properties. Increased levels of S100 B are associated with neurodegenerative disorders, including schizophrenia. The aim of the present study was to investigate the role of oxidative cell damage in the pathogenesis of schizophrenia. Forty patients who fully met the fourth Diagnostic and Statistical Manual of Mental Disorders criteria for schizophrenia and 35 healthy control subjects were included in the study. Serum S100 B level was determined to investigate brain damage. Plasma malondialdehyde (MDA) levels and susceptibility of red blood cell (RBC) to oxidation were determined to investigate the oxidative status and plasma vitamin E, vitamin C, serum total carotenoid levels and total antioxidant capacity and RBC superoxide dismutase (SOD) and whole blood glutathione peroxidase activities were measured to investigate the antioxidative defence before and after 6 weeks of antipsychotic treatment. Plasma MDA and serum S100 B levels and RBC-SOD activity were significantly higher in the schizophrenia group than those of the control group. Treatment did not modify any of the oxidative-antioxidative system parameters or serum S100 B levels. S100 B level was significantly higher in patients with negative symptoms than the patients with positive symptoms and the control subjects. S100 B levels were significantly reduced after 6 weeks of treatment in patients with negative symptoms. The results of the present study might support the oxidative cell injury hypothesis of the schizophrenia. Furthermore, the underlying mechanisms of the subgroups of schizophrenia might be different as suggested by the increased S100 B levels and its decrement after treatment in patients with negative symptoms.     

自由基代谢与精神分裂症临床症状和药物治疗的关系

目的：探讨自由基代谢与精神分裂症临床症状和药物治疗的关系。方法：是否治疗的慢性精神分裂症患者各４０例分别评定定阳性和阴性症状量表（ＰＡＮＳＳ）,并测定膜脂质过氧化物丙二醛（ＭＤＡ）含量、铜／锌超氧化物歧化酶（Ｇｕ－ＺｎＳＯＤ）和谷胱苷肽过氧化物酶（ＧＳＨ－Ｐｘ）活性。结果：与健康对照组相比,未治疗组患者ＭＤＡ含量和ＧＳＨ－Ｐｘ活性显著增加,治疗组患者无显著改变;而两组患者ＳＯＤ活性显著降低;未治疗     

Serum glutathione peroxidase,xanthine oxidase,and superoxide dismutase activities and malondialdehyde levels in patients with Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Oxidative stress has been hypothesized to play a major role in the development of PD in various studies. This study assessed to investigate oxidative and anti-oxidative status in PD patients. We evaluated oxidant/antioxidant status by measuring serum malondialdehyde (MDA) levels, xanthine oxidase (XO) activities, and activities of antioxidant enzymes, namely, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). The study included 29 patients with PD and 32 healthy subjects as controls. Comparison of oxidative parameters in the patient and control groups revealed significantly higher GSH-Px and XO activities in the patient group. Serum MDA and SOD activities in PD patients were not significantly different from the controls. MDA was negatively correlated with duration of the PD and positively with age of onset. There was a negative correlation between SOD and Hoehn and Yahr (H&Y) stage. According to these results, we suggest that oxidative stress may contribute to the development of PD.     

Serum selenium and plasma malondialdehyde levels and antioxidant enzyme activities in patients with obsessive-compulsive disorder

There is mounting evidence indicating that reactive free radical species are involved in initiation and development of many different forms of human pathologies including psychiatric disorders. In the present study, we aimed to determine whether serum selenium (Se), antioxidant enzyme (glutathione peroxidase, GSH-Px, superoxide dismutase, SOD, and catalase, CAT) activities, and plasma malondialdehyde (MDA) levels, a product of lipid peroxidation, were associated with obsessive-compulsive disorder (OCD). The participants were 28 patients with OCD that were drug-free at least for a month and a control group (n=28) of healthy subjects, matched with respect to age and sex. In both groups, the levels of the erythrocyte MDA, GSH-Px, SOD, Se, and the CAT were measured. The levels of MDA and SOD were statistically significantly higher (p<0.01, p<0.05 respectively) in patients than controls. The activities of CAT, GSH-Px, and serum Se levels were statistically significantly lower (p<0.0001, p<0.001, and p<0.001 respectively) in patients than controls. There was a positive correlation in patients between plasma GSH-Px activity and Se concentration (r=52, p=0.001). However, in patients with OCD, CAT and SOD activities were significantly and negatively correlated with MDA levels (r=-0.45, p=0.017 for CAT and r=-0.54, p=0.020 for SOD). The study shows the presence of a significant relationship of OCD and oxidative stress, and consequently, an involvement of free radicals and of the antioxidant defence.     

Oxidative damage and schizophrenia: the potential benefit by atypical antipsychotics

There is evidence to suggest the derangement of the oxidant and antioxidant defense system in schizophrenia. The present study examined the effect of atypical antipsychotics on lipid peroxidation, superoxide dismutase (SOD) and ascorbic acid. For this purpose, a prospective, open-label, 8-week study design was utilized. Serum SOD, serum malondialdehyde (MDA) and plasma ascorbic acid were estimated. Schizophrenic patients (n = 48) were compared with age- and sex-matched healthy volunteers (n = 40). There was a significant increase in serum SOD, serum MDA and a decrease in plasma ascorbic acid in schizophrenic patients as compared to control subjects. The trend altered significantly after the treatment with atypical antipsychotics. The results of the Brief Psychiatric Rating Scale for schizophrenia also improved with the treatment. The findings indicate an involvement of free radicals in schizophrenia and its modification by treatment with atypical antipsychotics. This study can also be used as a predictor of drug response by atypical antipsychotics in schizophrenia.     

The role of oxidative stress in postoperative delirium

AIM: This study aimed to determine a marker that predicts delirium using preoperative oxidative processes in patients undergoing cardiopulmonary bypass surgery. METHOD: Twelve of the 50 patients included in the study showed signs of delirium during postoperative follow-up. The Delirium Rating Scale was used in patients with delirium according to DSM-IV-TR in the postoperative period. Venous blood samples were obtained from the patients the day before and the day after the surgery to determine plasma antioxidant enzyme levels. RESULTS: While there were no differences in preoperative superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) levels in both groups, catalase (CAT) levels were significantly lower in the delirium group. Postoperative SOD and MDA levels were also higher in the delirium group, while the GSH-Px levels were found to be lower when compared with those during the preoperative period. In the nondelirium group, the postoperative MDA and GSH-Px levels were found to be lower than preoperative levels, and postoperative SOD levels were found to be higher than preoperative levels. CAT levels were lower in the delirium group when the pre- and postoperative levels were compared in both groups. The postoperative levels of SOD, GSH-Px and CAT in the nondelirium group and MDA in the delirium group were significantly higher than preoperative levels. CONCLUSION: Patients with low preoperative CAT levels appeared to be more susceptible to delirium than patients with higher CAT levels.     

丁苯酞辅助治疗对老年痴呆症患者的疗效

目的探讨丁苯酞辅助治疗对老年痴呆症患者的疗效及其可能的机制。方法本研究对象为2018年1月~2019年8月我院收治的88例老年痴呆症患者,按照数字表法随机均分为两组,每组44人,对照组给予常规治疗,观察组在此基础上联合丁苯酞治疗。比较两组患者治疗前后病理行为评分表(BEHA VE-AD)、生活能力量表(ADL)、简易精神状况检查表(MMSE)等量表,检测和比较血清β淀粉样蛋白(Aβ)水平,血清谷胱甘肽过氧化物酶(GSH-Px)、丙二醛(MDA)、超氧化物歧化酶(SOD)等氧化应激指标,内皮素(ET-1)、血管内皮生长因子(VEGF)等血管内皮功能指标。结果治疗后两组ADL评分、MMSE评分均升高,血清Aβ水平、BEHA VE-AD评分均降低,且治疗后观察组各项指标均优于对照组(P<0.05);治疗后两组血清GSH-Px、SOD水平升高,MDA水平降低,且治疗后观察组各项指标均优于对照组(P<0.05);治疗后两组血清ET-1水平均降低,VEGF水平均升高,且治疗后观察组各项指标均优于对照组(P<0.05)。结论丁苯酞辅助治疗能够更有效的提升老年痴呆症患者的认知及生活能力,可能与其促进血清Aβ水平降低,减轻氧化应激,提升血管内皮功能有关。     

Human plasma glutathione peroxidase and symptom severity in schizophrenia.

BACKGROUND: Previous studies have shown impaired antioxidant defense system in schizophrenia, including alterations in glutathione peroxidase (GSH-Px) activity in erythrocytes. There exists a related enzyme, human plasma GSH-Px (hpGSH-Px), that has not been previously examined in schizophrenia. METHODS: An enzyme-linked immunoassay was used to determine hpGSH-Px levels in male schizophrenic patients (n = 39), using a within-subject, on-off haloperidol (HD) treatment design, compared with age- and gender-matched normal control subjects (n = 37). RESULTS: hpGSH-Px was not significantly different between normal control subjects and patients, consistent with our previous findings in erythrocyte GSH-Px. There were no significant treatment effects. hpGSH-Px was significantly and positively correlated with psychosis rating scores in patients both on and off HD treatment. CONCLUSIONS: Although not different from normal controls, hpGSH-Px levels in patients may reflect oxidative stress associated with greater psychosis severity. The present findings thus suggest that schizophrenic patients, without obvious increase of endogenous antioxidant enzymes (e.g., hpGSH-Px), may be at risk for oxidative damage.     

Antioxidant enzyme and malondialdehyde values in social phobia before and after citalopram treatment

A growing body of evidence indicates that oxidative stress is involved in the etiopathogenesis of some psychiatric disorders. In our previous study, we have found that social phobia (SP) seems to be associated with elevated antioxidant enzymes and malondialdehyde (MDA) levels, a lipid peroxidation product. In the present investigation, we sought to determine whether the increased radical burden observed in patients with SP would be attenuated with alleviation of symptoms. Thirty-nine patients diagnosed with generalized SP and 39 healthy controls participated in this study. The measurements of MDA, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were performed before and after a period of 8 weeks of citalopram treatment. In this period, the patients received citalopram but controls did not. The initial dose of citalopram was 20mg, with 20 mg increments occurring every 2 weeks, to a maximum dose of 60 mg, with the mean daily dose of 38.9 +/- 13.3 mg/day. All patients were evaluated by using Liebowitz Social Anxiety Scale (LSAS). The mean MDA, SOD, GSH-Px and CAT levels of the patient group at baseline were significantly higher than those of controls. Antioxidant enzymes and MDA levels decrease significantly through citalopram treatment. Significant and positive correlation was observed between decrease in the total LSAS scores, and SOD or CAT levels. In conclusion, our results suggest that, in patients with SP, subchronic treatment with citalopram may decrease antioxidant enzymes and MDA values and that they are state markers of SP because they return to normal values with treatment.     

Impaired antioxidant status and reduced energy metabolism in autistic children

Accumulating evidence suggests that oxidative stress induced mechanisms are believed to be associated with the pathophysiology of autism. In this study, we recruited 19 Omani autistic children with age-matched controls to analyze their plasma and serum redox status and the levels of ATP, NAD⁺ and NADH using well established spectrophotometric assays. A significant decrease was observed in the levels of plasma total antioxidants (TA), reduced glutathione (GSH), superoxide and catalase activity in Omani autistic children as compared to their age-matched controls. In contrary, the level of plasma glutathione peroxidase (GSH-Px) was significantly increased in autistic children. Reduced serum NAD⁺ and ATP levels and lower NAD⁺:NADH ratio were observedin patients with autism compared to controls. Finally, a significant inverse correlation was observed between plasma GSH, SOD, catalase activity, and serum NAD⁺ and ATP levels, and autism severity using Childhood Autism Rating Scale (CARS) scores. The levels of plasma GSH-Px and serum NADH correlated strongly with autism severity whilst no significant correlation was observed for plasma TA. Our data suggests that increased vulnerability to oxidative stress in autism may occur as a consequence of alterations in antioxidant enzymes leading to mitochondrial dysfunction.     

The ALDH2 and 5-HT2A genes interacted in bipolar-I but not bipolar-II disorder

Objective

Many physiological and pathological processes, such as infections, environmental toxins, and ionizing radiation increase bodily concentrations of oxidizing substances, known as free radicals, which lead to neurodegenerative disorders. Sleep is one of the most important factors contributing to health; however, insomnia is among the most prevalent health complaints.

Methods

In this study, for the first time in the literature, we investigated the effects of primary insomnia on certain oxidative stress biomarkers. For this purpose, glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and myeloperoxidase (MPO) activities and levels of reduced glutathione (GSH) and malondialdehyde (MDA) were measured in 30 patients with primary insomnia and 30 healthy volunteers

Results

Our results show that the patients with primary insomnia had significantly lower GSH-Px activity and higher MDA levels compared with the controls.

Conclusion

These results may indicate the important role of sleep in attenuating oxidative stress.     

Antioxidative–oxidative balance in epilepsy patients on antiepileptic therapy: a prospective case–control study

Oxidative stress has been implicated in various disorders, including epilepsy. The aim of this study was to investigate the oxidant and antioxidant status of patients with epilepsy using antiepileptic drugs regularly and to compare them with healthy subjects. We investigated serum catalase (CAT), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and xanthine oxidase (XO) levels in 58 epilepsy patients and 25 healthy controls. Patients were divided into polytherapy (n = 17) and monotherapy (n = 41) groups, and antioxidant status was compared between the two groups and controls. There was no significant difference between the patient and control groups in terms of age or gender (p > 0.05). The mean duration of illness in the patients was 14.8 years, and the mean duration of treatment was 11.4 years. Comparison of the patient and control groups in terms of oxidative stress and antioxidant defence parameters revealed significantly higher MDA, GSH-Px, XO and lower level of CAT, SOD levels (p < 0.05). There were no differences in CAT, MDA, GSH-Px or SOD levels between the monotherapy and polytherapy groups; but the XO level was higher in the monotherapy group (p < 0.05). Although the XO level was decreased by polytherapy, it was higher than in controls. Our study found significantly low level of antioxidants in patients with epilepsy as compared to control. Thus, antiepileptic treatment did not improve oxidative stress parameters. Furthermore, our results show that polytherapy does not change the situation as compared with monotherapy. Antioxidant replacement therapy may benefit these patients.     

Altered Antioxidant Defenses in Drug-Naive First Episode Patients with Schizophrenia Are Associated with Poor Treatment Response to Risperidone: 12-Week Results from a Prospective Longitudinal Study

Abnormal redox regulation is thought to contribute to schizophrenia (SCZ). Accumulating studies have shown that the plasma antioxidant enzyme activity is closely associated with the course and outcome in antipsychotics-naïve first-episode (ANFE) patients with SCZ. The main purpose of this study was to investigate the effect of risperidone on oxidative stress markers in ANFE patients and the relationship between risperidone response and changes in oxidative stress markers. Plasma activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) enzyme, total antioxidant status (TAS), and malondialdehyde (MDA) levels were measured in 354 ANFE patients and 152 healthy controls. The clinical symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS). Patients received risperidone monotherapy for 12 weeks and oxidative stress markers and PANSS were measured at baseline and at follow-up. Compared with healthy controls, the patients exhibited higher activities of SOD, CAT, and TAS levels, but lower MDA levels and GPx activity. A comparison between 168 responders and 50 non-responders at baseline and 12-week follow-up showed that GPx activity decreased in both groups after treatment. Moreover, GPx activity decreased less in responders and was higher in responders than in non-responders at follow-up. These results demonstrate that the redox regulatory system and antioxidant defense enzymes may have predictive value for the response of ANFE patients to risperidone treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01036-3.Key Words: Schizophrenia, Oxidative stress, Antioxidant defense system, Clinical response, Risperidone     

The novel oxidative stress marker thioredoxin is increased in first-episode schizophrenic patients

Excessive free radical production leading to oxidative stress may be involved in the pathophysiology of schizophrenia. Oxidative stress increases serum thioredoxin (TRX), a redox-regulating protein with antioxidant activity recognized as an oxidative-stress marker. The aim of this study was to assess the clinical significance of serum TRX levels in various stages of schizophrenia. Serum TRX levels were determined using ELISA from 60 never-medicated first-episode and 66 medicated chronic schizophrenia patients and 66 healthy control subjects matched for age and gender. The psychopathology of schizophrenia was assessed by the Positive and Negative Syndrome Scale (PANSS). Our results showed that group comparison between first-episode and chronic patients and control groups revealed significantly increased serum TRX only in first-episode patients. Increased levels of TRX in patients experiencing an acute stage schizophrenic episode was also significantly higher compared to chronic schizophrenic patients on antipsychotic medication. Serum TRX was also positively correlated with positive symptoms of schizophrenia. Our results suggest oxidative stress occurs in an acute stage of schizophrenic episode and may have an important role in pathogenesis and symptomology of schizophrenia. Lower TRX levels in chronic patients treated with antipsychotics may have implications for treatment outcome.     

Altered antioxidant defense system in clinically stable patients with schizophrenia and their unaffected siblings

Objective

To determine Red Blood Cell (RBC) antioxidant enzyme activities and plasma Thiobarbituric Acid Reactive Substances (TBARS) in clinically stable patients with schizophrenia and their unaffected siblings.

Methods

A case-control study carried out on three groups: 60 schizophrenic patients treated with neuroleptics, 33 of their unaffected siblings and 30 healthy controls with no family psychiatric history. Biological markers were measured on fasting patients after a period of tobacco abstinence: RBC antioxidant enzyme activities – superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) – by spectrophotometry and plasma levels of TBARS by spectrofluorimetry.

Results

RBC SOD and CAT activities were significantly lower in schizophrenic patients and their unaffected siblings compared to the control group (P < 0.001). Schizophrenic patients also had significantly lower RBC GSH-Px activity than controls (P = 0.03), whereas their unaffected siblings had significantly higher RBC GSH-Px activity than controls (P = 0.04). Plasma TBARS were higher in schizophrenic patients than their unaffected siblings: 2.1 ± 0.8 μmol/l vs. 1.7 ± 0.6 μmol/l (P = 0.06).

Conclusions

Our results showed a decrease in antioxidant enzyme activities and an increase in lipid peroxidation confirming the existence of oxidative stress in schizophrenic patients treated with neuroleptics. Additionally, this suggests that the increase in GSH-Px activity in unaffected siblings would be a protective mechanism against oxidative stress and damage. Other studies are necessary to confirm these findings.     

Dose response of ethanol ingestion on antioxidant defense system in rat brain subcellular fractions

This study investigated the response of the antioxidant defense system in brain subcellular fractions after oral graded doses of ethanol to rat. Four groups of male Fischer-344 rats were orally administered saline, ethanol 2 g, 4 g, and 6 g/kg, respectively, and sacrificed 1 hour post treatment. Brain cytosol, synaptosomes, microsomes and mitochondria were separated by density gradient differential centrifugation and assayed for antioxidant system. A significant and dose-dependent-decrease in superoxide dismutase (SOD) activity was observed in all brain subcellular fractions. Catalase (CAT) activity was significantly decreased in brain mitochondria (67% and 80% of control) at higher doses of ethanol; whereas, CAT activity was significantly increased in cytosol, synaptosomes and microsomes. Glutathione peroxidase (GSH-Px) activity was significantly increased in all brain subcellular fractions except in cytosol at higher dose of ethanol. Malondialdehyde (MDA) content was significantly increased in all brain subcellular fractions showing dose response of ethanol-induced oxidative stress. The increase in MDA levels in the brain synaptosomes and microsomes were higher at 6 g dose of ethanol (155% and 163% of control) when compared to mitochondria and cytosol. Glutathione (GSH) levels were significantly increased in brain cytosol and microsomes at higher dose of ethanol (164% and 159% of control); whereas, the GSH concentration was significantly decreased in brain synaptosomes and mitochondria. The antioxidant enzyme (AOE) activity ratios (GSH-Px/SOD and GSH-Px + CAT/SOD) were dose dependently increased in all brain subcellular fractions, particularly in synaptosomes. The GSH/GSSG ratio was dose dependently increased in brain microsomes. The perturbations in the antioxidant defense system and enhanced lipid peroxidation following graded doses of ethanol ingestion indicate a dose-dependent-oxidative 2133stress response in brain subcellular compartments of rats.