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

doi:10.1016/j.pnpbp.2007.08.003

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Volume 32, Issue 1, 1 January 2008, Pages 155-159

https://doi.org/10.1016/j.pnpbp.2007.08.003 Get rights and content

Abstract

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.

Introduction

Reactive oxygen species (ROS) are oxygen-containing molecules that have a higher reactivity than ground state molecular oxygen. ROS include free radicals such as the superoxide anion radical (O₂⁻) and the hydroxyl radical (^.OH), and molecules such as singlet oxygen (¹O₂) and hydrogen peroxide (H₂O₂). Free radicals, formed in tissues, have very short half-lifes, and thus determination of their levels is difficult (Kuloglu et al., 2002). However, they can be evaluated indirectly by the measurement of antioxidant enzyme levels such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and plasma Thiobarbituric Acid Reactive Substances (TBARS) as an indicator of free radical-induced lipid peroxidation (Halliwell, 1999, Gutteridge and Halliwell, 2000).

Recently, there has been abundant evidence that free radicals are involved in membrane pathology in the central nervous system (CNS) and may play a role in many diseases such as schizophrenia (Lohr, 1991, Mahadik and Mukherjee, 1996, Yao et al., 2001, Yao et al., 2004, Reddy et al., 2003, Fendri et al., 2006). Schizophrenia, a serious hereditary disease, is a biological disorder of the brain resulting from abnormalities that arise early in life and disrupt normal development of the brain. The chemical nature of the schizophrenic brain is still not completely understood. Oxidative stress damage might be the biochemical basis of the neurodevelopmental abnormalities in schizophrenia (Horrobin, 1998).

Observations on the role of oxidative stress, the imbalance between the formation of reactive oxygen species and the activity of Antioxidant Defense System (AODS) in schizophrenia have been controversial (Reddy et al., 1991, Mahadik and Mukherjee, 1996, Reddy and Yao, 1996, Kuloglu et al., 2002, Reddy et al., 2003). Impaired antioxidant enzyme defense and increased lipid peroxidation have been reported in chronic-medicated (Herken et al., 2001, Khan et al., 2002) and in drug-naïve first-episode schizophrenic patients (Mukherjee et al., 1996, Mahadik et al., 1998, Reddy et al., 2003).

Large numbers of studies have shown that schizophrenia runs in families, that is, the morbid risk of developing schizophrenia increases with the greater genetic relatedness to an individual with the disorder (Hovatta et al., 1997, Tsuang et al., 1999). No known reports relate to oxidative stress markers in genetically vulnerable subjects, such as first degree relatives of schizophrenic patients.

In the present study, Red Blood Cell (RBC) antioxidant enzyme (SOD, GSH-Px and CAT) activities and plasma TBARS were determined in clinically stable patients with schizophrenia and their unaffected siblings.

Section snippets

Methods

A case-controlled study was conducted during the first semester 2003 in a collaboration between the Biophysics Laboratory of the Faculty of Medicine and the Psychiatry Department of the University Hospital of Monastir.

Antioxidant enzyme activities

RBC antioxidant activities of SOD and CAT were not related to age and not affected by gender or smoking for each group, whereas RBC antioxidant GSH-Px activity correlated positively with age in unaffected siblings of schizophrenic patients (r = 0.41, P = 0.02) and in control subjects (r = 0.37, P = 0.06). Thus, differences in the RBC antioxidant GSH-Px activity between the study groups were tested by performing an ANOVA, adjusted by age. Schizophrenic patients and their unaffected siblings had

Discussion

The major findings of the present study were that (1) RBC activities of SOD, CAT and GSH-Px were decreased in clinically stable schizophrenic patients treated with neuroleptics; (2) there were differential alterations in antioxidant enzyme activities in their unaffected siblings; (3) Plasma TBARS were high in schizophrenic patients; (4) Plasma TBARS were not related to RBC antioxidant enzyme activities in all groups. These findings suggest that schizophrenic patients, with the decrease in

Conclusion

The results obtained 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. On the other hand, in unaffected siblings, genetically vulnerable subjects, SOD and CAT levels were significantly lower whereas GSH-Px antioxidant activity was significantly increased compared to control subjects. The increase in GSH-Px antioxidant activity in unaffected siblings may be a

Acknowledgments

We thank the participants in our study and Moncef Rassas (Faculty of Medicine of Monastir) and Susan Gamon (Trace Element- Institute for UNESCO) for their valuable help with an earlier draft of this article.

References (40)

O. Akyol et al.
The indices of endogenous oxidative and antioxidative processes in plasma from schizophrenic patients. The possible role of oxidant/antioxidant imbalance
Prog Neuropsychopharmacol Biol Psychiatry
(2002)
O. Akyol et al.
Association between Ala-9Val polymorphism of Mn-SOD gene and schizophrenia
Prog Neuropsychopharmacol Biol Psychiatry
(2005)
T.D. Buckman et al.
Platelet glutathione peroxidase and monoamine oxidase activity in schizophrenics with CT scan abnormalities: relation to psychosocial variables
Psychiatry Res
(1990)
D.R. Evans et al.
Red blood cell membrame essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment
Prostaglandins Leukot Essent Fatty Acids
(2003)
C. Fendri et al.
Oxidative stress involvement in schizophrenia pathophysiology: a review
Encephale
(2006)
C.S. Gama et al.
Elevated serum peroxide dismutase and thiobarbituric acid reactive substances in schizophrenia: a study of patients treated with haloperidol or clozapine
Prog Neuropsychopharmacol Biol Psychiatry
(2006)
S. Grignon et al.
Assessment of malondialdehyde levels in schizophrenia: A meta-analysis and some methodological considerations
Prog Neuropsychopharmacol Biol Psychiatry
(2007)
G. Grima et al.
Dopamine induced oxidative stress in neurons with glutathione deficit: implication for schizophrenia
Schizophr Res
(2003)
D.F. Horrobin
The membrane phospholipids hypothesis as a biochemical basis for the neurodevelpmental concept of schizophrenia
Schizophr Res
(1998)
M.M. Khan et al.
Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics
Schizophr Res
(2002)

S.P. Mahadik et al.

Free radical pathology and antioxidant defense in schizophrenia: a review

Schizophr Res

(1996)

S.P. Mahadik et al.

Elevated plasma lipid peroxides at the onset of nonaffective psychosis

Biol Psychiatry

(1998)

S. Mukherjee et al.

Impaired antioxidant defense at the onset of psychosis

Schizophr Res

(1996)

P.K. Ranjekar et al.

Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schizophrenic and bipolar mood disorder patients

Psychiatry Res

(2003)

R.D. Reddy et al.

Free radical pathology in schizophrenia: a review

Prostaglandins Leukot Essent Fatty Acids

(1996)

R.D. Reddy et al.

Enzymes of the antioxidant defense system in chronic schizophrenic patients

Biol Psychiatry

(1991)

R.D. Reddy et al.

Reduced plasma antioxidants in first-episode patients with schizophrenia

Schizophr Res

(2003)

K. Yagi

Assay for plasmalipid peroxides

Methods Enzymol

(1984)

J.K. Yao et al.

Effects of haloperidol on antioxidant defense system enzymes in schizophrenia

J Psychiatr Res

(1998)

J.K. Yao et al.

Human plasma glutathione peroxidase and symptom severity in schizophrenia

Biol Psychiatry

(1999)

Cited by (94)

Effects of antipsychotics on antioxidant defence system in patients with schizophrenia: A meta-analysis
2022, Psychiatry Research
Theory of oxidative stress is suggested in the pathophysiology of schizophrenia. To determine the cause of impaired antioxidant defense system in schizophrenia, a meta-analysis was performed by selecting studies published from 1964 to 2021 from Pubmed and Scopus databases. Data were analysed using Comprehensive Meta-Analysis version 2 and calculated effect sizes were compared between unmedicated and medicated patients with schizophrenia and healthy controls. Heterogeneity, publication bias assessments and subgroup analyses of drug-free and drug-naïve patients, and patients treated with atypical and typical antipsychotics were conducted. Subgroup analysis of confounding factors including age, gender, illness duration and patient status was also conducted. We found that glutathione peroxidase (GPx) was significantly decreased in all patients. Significantly lower catalase (CAT), glutathione (GSH) and albumin (ALB) were found in unmedicated patients only. Both groups showed significantly weakened non-enzymatic antioxidant capacity. Subgroup analyses indicated that weakened non-enzymatic antioxidant capacity may be associated with schizophrenia. Antioxidant status was more impaired in drug-free patients compared with other subgroups. This indicated that antipsychotics may improve antioxidant defense system. Although effect sizes were smaller, future studies may focus on the effect of antipsychotic discontinuation. In overall, schizophrenia was associated with impaired antioxidant defense system especially the non-enzymatic antioxidant system.
Blood-based oxidation markers in medicated and unmedicated schizophrenia patients: A meta-analysis
2022, Asian Journal of Psychiatry
Increased reactive species due to the effect of antipsychotics on oxidative stress may be involved in the development of schizophrenia. However, antipsychotics may have different direct antioxidant effects due to their chemical structures. The present meta-analysis aimed to investigate whether the cause increased oxidant status in schizophrenia patients is due to the illness or induction by antipsychotics. Studies published from 1964 to 2021 were selected from Pubmed and Scopus databases. Data were analysed using Comprehensive Meta-Analysis version 2. Effect sizes were calculated and compared between unmedicated and medicated patients and healthy controls. Heterogeneity and publication bias were assessed. Subgroup analyses were conducted on drug-free and drug-naïve patients, and patients treated with atypical and typical antipsychotics. We found that medicated patients had significantly higher malondialdehyde (MDA), thiobarbituric acid reactive substances (TBARS) and total oxidant status (TOS). Meanwhile, significantly increased plasma/serum MDA and nitric oxide (NO) were observed in unmedicated patients only. Higher lipid peroxidation in the drug-naïve group may be associated schizophrenia. However, both atypical and typical antipsychotics may worsen lipid peroxidation. Antipsychotic discontinuation in the drug-free group led to significantly increased plasma/serum NO, with larger effect size than the atypical antipsychotic group. In conclusion, medicated schizophrenia patients were more suffered from increased oxidative stress. Therefore, future study may focus on the mechanism of action of specific antipsychotic on oxidative stress.
Chronic exposure to bisphenol S induces oxidative stress, abnormal anxiety, and fear responses in adult zebrafish (Danio rerio)
2021, Science of the Total Environment
Bisphenol S (BPS) is increasingly used in a wide range of industrial and consumer products, resulting in its ubiquitous distribution across the environment, including aquatic ecosystems. Although it is commonly known as a weak/moderate estrogenic compound, there has been a growing acknowledgment of the potential of BPS to cause toxicity by inducing oxidative stress. Oxidative stress is a major participant in the development of anxiety-like behaviors in humans and animals. Therefore, the present study was designed to examine the impact of BPS on anxiety-like behavior and fear responses in adult zebrafish and also to elucidate the possible linkage between the BPS neurotoxicity and oxidative status of the brain. To this end, adult male and female zebrafish were exposed to 0 (control), 1, 10, and 30 μg/L of BPS and 1 μg/L of 17-β-estradiol (E2) for 75 days. Following exposure, changes in anxiety and fear-related responses were evaluated by applying a novel tank test and by exposing focal fish to chemical alarm cues. Additionally, we evaluated the expression of multiple antioxidant genes in the zebrafish brain. Our results indicate that BPS, irrespective of exposure concentration, and E2 significantly decreased bottom-dwelling behavior and the latency to enter the upper water column. Furthermore, exposure to the highest concentration of BPS and E2 induced a significant decrease in fear-related responses. The impaired anxiety and reduced fear-related responses were associated with a down-regulation in the transcription of genes involved in enzymatic antioxidant defense. Taken together, our results suggest that chronic exposure to BPS impairs anxiety and fear responses in adult zebrafish, possibly by inducing oxidative stress in the brain.
Stress, psychiatric disorders, molecular targets, and more
2019, Progress in Molecular Biology and Translational Science
Mental health is central to normal health outcomes. A widely accepted theory is that chronic persistent stress during adulthood as well as during early life triggers onset of neuropsychiatric ailments. However, questions related to how that occurs, and why are some individuals resistant to stress while others are not, remain unanswered. An integrated, multisystemic stress response involving neuroinflammatory, neuroendocrine, epigenetic and metabolic cascades have been suggested to have causative links. Several theories have been proposed over the years to conceptualize this link including the cytokine hypothesis, the endocrine hypothesis, the oxidative stress hypothesis and the oxido-neuroinflammation hypothesis. The data discussed in this review describes potential biochemical basis of the link between stress, and stress-induced neuronal, behavioral and emotional deficits, providing insights into potentially novel drug targets.
Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients
2018, Psychiatry Research
To determine the relationship between alterations in the activity of the enzymes participating in antioxidative defense system and neurological soft signs (NSS) in schizophrenic patients with the first episode psychosis (S_FE, n = 19), patients in relapse (S_R, n = 46), and healthy controls (HC, n = 20). NSS intensity and enzymatic plasma activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) were compared between S_FE, S_R and HC subjects and a follow-up correlation analyses between the enzyme activities and NSS intensity was performed. NSS intensity was increased four times in schizophrenic patients compared with healthy controls. Activities of SOD and CAT were 40% decreased in S_FE and these reductions were ameliorated by antipsychotic treatment. GPX activity was 20% decreased in both patient groups compared with controls. A negative correlation between NSS intensity and GPX activity was specifically found in the S_FE patients. The data in this report argue that a reduction of GPX activity might be one of the causes for the emergence of NSS at the onset of schizophrenia, and provide the evidence that antipsychotic therapy can attenuate activity reductions of SOD and CAT, but not the activity reduction of GPX and the intensity of NSS.
Changes in behavioural parameters, oxidative stress and neurotrophins in the brain of adult offspring induced to an animal model of schizophrenia: The effects of FA deficient or FA supplemented diet during the neurodevelopmental phase
2018, Progress in Neuro-Psychopharmacology and Biological Psychiatry
A deficiency of maternal folic acid (FA) can compromise the function and development of the brain, and may produce a susceptibility to diseases such as schizophrenia (SZ) in the later life of offspring. The aim of this study was to evaluate the effects of both FA deficient and FA supplemented diets during gestation and lactation on behavioural parameters, the markers of oxidative stress and neurotrophic factors in adult offspring which had been subjected to an animal model of SZ. Female mother rats (Dam's) were separated into experimental maternal groups, which began receiving a special diet (food) consisting of the AIN-93 diet, a control diet, or an FA deficient diet during the periods of pregnancy and lactation. Dam's receiving the control diet were further subdivided into four groups: one group received only control diet, while three groups to receive supplementation with FA at different doses (5, 10 and 50 mg/kg). Adult offspring bred from the Dam's were divided into ten groups for induction of the animal model of SZ through the administration of ketamine (Ket) (25 mg/kg). After the last administration of the drug, the animals were subjected to the behavioural tests and were then euthanized. The frontal cortex (FC) and hippocampus (Hip) were then dissected for later biochemical analysis. Our data demonstrates that Ket induced the model of SZ by altering the behavioural parameters (e.g. hyperlocomotion, social impairment, deficits in the sensory-motor profile and memory damage in the adult animals); and also caused changes in the parameters of oxidative stress (lipid hydroperoxide – LPO; 8-isoprostane – 8-ISO; 4-hydroxynonenal – 4-HNE; protein carbonyl content; superoxide dismutase – SOD and catalase – CAT) as well as in the levels of neurotrophic factors (brain-derived neurotrophic factor – BDNF and nerve growth factor – NGF) particularly within the FC of adult offspring. A deficiency in maternal FA, alone or in combination with ket, was able to induce hyperlocomotion and social impairment in the offspring with increased levels of lipid and protein damage (LPO, 8-ISO, 4-HNE, carbonylation of protein) within the FC, increased activity of antioxidant enzymes (SOD and CAT) in both of the brain structures studied, and also reduced the levels of neurotrophins (BDNF and NGF), particularly within the Hip of the adult offspring. Supplementation of FA (5, 10 and 50 mg/kg) to the Dam's was mostly able to prevent the cognitive damage which was induced by Ket in the adult animals. FA (10 and 50 mg/kg) attenuated the action of Ket in the animals in relation to the biochemical parameters, proving the possible neuroprotective effect of FA in the adulthood of offspring that were subjected to the animal model of SZ. Our study indicates that the intake of maternal FA during pregnancy and lactation plays an important role, particularly in the regulation of markers of oxidative stress and neurotrophins.

View all citing articles on Scopus

View full text

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

Abstract

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Antioxidant enzyme activities

Discussion

Conclusion

Acknowledgments

Prog Neuropsychopharmacol Biol Psychiatry

Prog Neuropsychopharmacol Biol Psychiatry

Psychiatry Res

Prostaglandins Leukot Essent Fatty Acids

Encephale

Prog Neuropsychopharmacol Biol Psychiatry

Prog Neuropsychopharmacol Biol Psychiatry

Schizophr Res

Schizophr Res

Schizophr Res

Schizophr Res

Biol Psychiatry

Schizophr Res

Psychiatry Res

Prostaglandins Leukot Essent Fatty Acids

Biol Psychiatry

Schizophr Res

Methods Enzymol

J Psychiatr Res

Biol Psychiatry