The indices of endogenous oxidative and antioxidative processes in plasma from schizophrenic patients The possible role of oxidant/antioxidant imbalance

There is great evidence in recent years that oxygen free radicals play an important role in the pathophysiology of schizophrenia. The present study was performed to assess the changes in plasma nitric oxide (NO) and thiobarbituric acid-reactive substances (TBARS) levels, and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and xanthine oxidase (XO) activities in schizophrenic patients compared to age- and sex-matched normal controls. A hundred patients with schizophrenia and 51 healthy volunteers were included in the study. XO, SOD, and GSH-Px activities as well as NO and TBARS levels were estimated by standard biochemical techniques in the plasma of normal healthy controls and schizophrenia patients. In schizophrenia, increased plasma XO activity (P < .0001) and NO levels (P < .0001), decreased SOD activity (P < .0001), and unchanged GSH-Px activity were detected compared to control group. Plasma TBARS levels were increased in schizophrenic patients (P < .01), especially in the residual subtype. TBARS levels in nonsmoker schizophrenic patients were found to be higher than nonsmoker controls. Although TBARS levels in both patients and controls were found to be higher in smokers as compared to nonsmokers, it was not statistically significant. No effects of duration of the illness, gender, and low and high dose of daily neuroleptic treatment equivalent to chlorpromazine on oxidant and antioxidant parameters were observed. Because the dose and the duration of treatment with drugs have no influence on the results, it can be interpreted that the findings are more likely to be related mainly to the underlying disease. These findings indicated a possible role of increased oxidative stress and diminished enzymatic antioxidants, both of which may be relevant to the pathophysiology of schizophrenia. On the other hand, increased NO production by nitric oxide synthetases (NOSs) suggests a possible role of NO in the pathophysiological process of schizophrenia. These findings may also suggest some clues for the new treatment strategies with antioxidants and NO synthase (NOS) inhibitors in schizophrenia.

[1]  P. Kuo,et al.  The Emerging Multifaceted Roles of Nitric Oxide , 1995, Annals of surgery.

[2]  S. Mukherjee,et al.  Impaired antioxidant defense at the onset of psychosis , 1996, Schizophrenia Research.

[3]  H. Herken,et al.  Red blood cell nitric oxide levels in patients with schizophrenia , 2001, Schizophrenia Research.

[4]  P. H. Evans,et al.  Free radicals in brain metabolism and pathology. , 1993, British medical bulletin.

[5]  Jeffrey K. Yao,et al.  Abnormal incorporation of arachidonic acid into platelets of drug-free patients with schizophrenia , 1996, Psychiatry Research.

[6]  S. Hirsch,et al.  Elevated platelet calcium mobilization and nitric oxide synthase activity may reflect abnormalities in schizophrenic brain. , 1995, Biochemical and biophysical research communications.

[7]  S. Barnes,et al.  Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. Formation of novel nitrogen-containing oxidized lipid derivatives. , 1994, The Journal of biological chemistry.

[8]  J. Laugharne,et al.  Essential fatty acid deficiency in erythrocyte membranes from chronic schizophrenic patients, and the clinical effects of dietary supplementation. , 1996, Prostaglandins, leukotrienes, and essential fatty acids.

[9]  M. Ackenheil,et al.  Coincidence of Schizophrenia and Hyperbilirubinemia , 1991, Pharmacopsychiatry.

[10]  David F. Horrobin,et al.  The membrane hypothesis of schizophrenia , 1994, Schizophrenia Research.

[11]  G. Weber,et al.  Malignant transformation‐linked imbalance: Decreased xanthine oxidase activity in hepatomas , 1975, FEBS letters.

[12]  K. A. Kirkebøen,et al.  The role of nitric oxide in sepsis – an overview , 1999, Acta anaesthesiologica Scandinavica.

[13]  D. Horrobin,et al.  Fatty acid levels in the brains of schizophrenics and normal controls , 1991, Biological Psychiatry.

[14]  M. Traber,et al.  Tobacco-related diseases. Is there a role for antioxidant micronutrient supplementation? , 2000, Clinics in chest medicine.

[15]  H. Meltzer,et al.  Genetic variant near cytosolic phospholipase A2 associated with schizophrenia , 1996, Schizophrenia Research.

[16]  P. Riederer,et al.  Characterization and regional distribution of nitric oxide synthase in the human brain during normal ageing , 1999, Brain Research.

[17]  C. Szabó,et al.  Peroxynitrite‐mediated oxidation of dihydrorhodamine 123 occurs in early stages of endotoxic and hemorrhagic shock and ischemia‐reperfusion injury , 1995, FEBS letters.

[18]  N. Tietz Fundamentals of Clinical Chemistry , 1970 .

[19]  T. Dawson,et al.  Gases as biological messengers: nitric oxide and carbon monoxide in the brain , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[20]  G. Rubanyi,et al.  Cytoprotective function of nitric oxide: inactivation of superoxide radicals produced by human leukocytes. , 1991, Biochemical and biophysical research communications.

[21]  G. Vaiva,et al.  [Erythrocyte superoxide dismutase (eSOD) determination in positive moments of psychosis]. , 1994, Therapie.

[22]  W. Valentine,et al.  Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. , 1967, The Journal of laboratory and clinical medicine.

[23]  S. Mukherjee,et al.  Elevated Plasma Lipid Peroxides at the Onset of Nonaffective Psychosis , 1998, Biological Psychiatry.

[24]  P. Lavori,et al.  Long-term treatment effects of vitamin E for tardive dyskinesia , 1998, Biological Psychiatry.

[25]  Jeffrey K. Yao,et al.  Human plasma glutathione peroxidase and symptom severity in schizophrenia , 1999, Biological Psychiatry.

[26]  S. Mahadik,et al.  Oxidative injury and potential use of antioxidants in schizophrenia. , 1996, Prostaglandins, leukotrienes, and essential fatty acids.

[27]  İ. Durak,et al.  A methodological approach to superoxide dismutase (SOD) activity assay based on inhibition of nitroblue tetrazolium (NBT) reduction. , 1993, Clinica chimica acta; international journal of clinical chemistry.

[28]  T. Miyaoka,et al.  Schizophrenia-associated idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome). , 2000, The Journal of clinical psychiatry.

[29]  J. Wettstein,et al.  On the effect of neonatal nitric oxide synthase inhibition in rats: a potential neurodevelopmental model of schizophrenia , 1999, Neuropharmacology.

[30]  X. Zhang,et al.  The Effect of Extract of Ginkgo Biloba Added to Haloperidol on Superoxide Dismutase in Inpatients With Chronic Schizophrenia , 2001, Journal of clinical psychopharmacology.

[31]  H. Herken,et al.  Evidence that the activities of erythrocyte free radical scavenging enzymes and the products of lipid peroxidation are increased in different forms of schizophrenia , 2001, Molecular Psychiatry.

[32]  W. Pryor,et al.  Oxidants in Cigarette Smoke Radicals, Hydrogen Peroxide, Peroxynitrate, and Peroxynitrite a , 1993, Annals of the New York Academy of Sciences.

[33]  R. Reddy,et al.  Free radical pathology in schizophrenia: a review. , 1996, Prostaglandins, leukotrienes, and essential fatty acids.

[34]  Sandra L. Whatley,et al.  Superoxide, neuroleptics and the ubiquinone and cytochrome b5 reductases in brain and lymphocytes from normals and schizophrenic patients , 1998, Molecular Psychiatry.

[35]  N. Cortas,et al.  Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method. , 1990, Clinical chemistry.

[36]  İ. Durak,et al.  Activities of free radical and DNA turn-over enzymes in cancerous and non-cancerous human brain tissues. , 1995, Redox report : communications in free radical research.

[37]  D. Horrobin,et al.  Gene targets related to phospholipid and fatty acid metabolism in schizophrenia and other psychiatric disorders: an update. , 2000, Prostaglandins, leukotrienes, and essential fatty acids.

[38]  H. Lal,et al.  Oxidative stress and role of antioxidant and ω-3 essential fatty acid supplementation in schizophrenia , 2001, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[39]  A. Elkashef,et al.  Vitamin E in the treatment of tardive dyskinesia. , 1990, The American journal of psychiatry.

[40]  N. Zisapel,et al.  Melatonin improves sleep quality of patients with chronic schizophrenia. , 2000, The Journal of clinical psychiatry.

[41]  J. Overall,et al.  The Brief Psychiatric Rating Scale , 1962 .

[42]  G. Sedvall,et al.  INCREASED CONTENT OF IMMUNOREACTIVE PROSTAGLANDIN E IN CEREBROSPINAL FLUID OF PATIENTS WITH SCHIZOPHRENIA , 1980, The Lancet.

[43]  R. Sandyk,et al.  Antioxidants in the treatment of schizophrenia. , 1992, The International journal of neuroscience.

[44]  Jeffrey K. Yao,et al.  Red blood cell membrane dynamics in schizophrenia. II. Fatty acid composition , 1994, Schizophrenia Research.

[45]  L. Cavallini,et al.  Decrease of serum malondialdehyde in patients treated with chlorpromazine. , 1987, Clinica chimica acta; international journal of clinical chemistry.

[46]  D. Kammen,et al.  Effects of haloperidol on antioxidant defense system enzymes in schizophrenia. , 1998, Journal of psychiatric research.

[47]  Jeffrey K. Yao,et al.  Reduced level of plasma antioxidant uric acid in schizophrenia , 1998, Psychiatry Research.

[48]  Increased manganese-superoxide dismutase activity in postmortem brain from neuroleptic-treated psychotic patients , 1996, Biological Psychiatry.

[49]  W. Wąsowicz,et al.  Optimized steps in fluorometric determination of thiobarbituric acid-reactive substances in serum: importance of extraction pH and influence of sample preservation and storage. , 1993, Clinical chemistry.

[50]  A. Var,et al.  Testicular nitric oxide levels after unilateral testicular torsion/detorsion in rats pretreated with caffeic acid phenethyl ester , 2000, Urological Research.

[51]  P. Rosenberg,et al.  Methylene blue adjuvant therapy of schizophrenia. , 1997, Clinical neuropharmacology.

[52]  W. Hall,et al.  Xanthine oxidase from human liver: purification and characterization. , 1986, Archives of biochemistry and biophysics.

[53]  J. Merrill,et al.  The kinetics and regulation of the induction of type II nitric oxide synthase and nitric oxide in human fetal glial cell cultures , 1997, Molecular Psychiatry.

[54]  T. Hanihara,et al.  Hypouricemia in chronic schizophrenic patients with polydipsia and hyponatremia. , 1997, The Journal of clinical psychiatry.

[55]  D. Horrobin,et al.  Phospholipases: in search of a genetic base of schizophrenia. , 1996, Prostaglandins, leukotrienes, and essential fatty acids.

[56]  Guy C. Brown Nitric oxide regulates mitochondrial respiration and cell functions by inhibiting cytochrome oxidase , 1995, FEBS letters.

[57]  D. Horrobin,et al.  A red cell membrane abnormality in a subgroup of schizophrenic patients: evidence for two diseases , 1994, Schizophrenia Research.

[58]  Jeffrey K. Yao,et al.  Membrane phospholipid abnormalities in postmortem brains from schizophrenic patients , 2000, Schizophrenia Research.

[59]  J. Rotrosen,et al.  Elevated PLA2 activity in schizophrenics and other psychiatric patients , 1993, Biological Psychiatry.

[60]  D. Horrobin,et al.  Plasma membrane phospholipid fatty acid composition of cultured skin fibroblasts from schizophrenic patients: comparison with bipolar patients and normal subjects , 1996, Psychiatry Research.

[61]  S. Johnson Micronutrient accumulation and depletion in schizophrenia, epilepsy, autism and Parkinson's disease? , 2001, Medical hypotheses.

[62]  James B. Mitchell,et al.  Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[63]  Y. Sun,et al.  A simple method for clinical assay of superoxide dismutase. , 1988, Clinical chemistry.

[64]  W. Fenton,et al.  Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia , 2000, Biological Psychiatry.

[65]  Y. Sagara Induction of Reactive Oxygen Species in Neurons by Haloperidol , 1998, Journal of neurochemistry.

[66]  R. Faull,et al.  Comparative proteome analysis of the hippocampus implicates chromosome 6q in schizophrenia , 2000, Molecular Psychiatry.

[67]  H. Schulman Nitric oxide: a spatial second messenger , 1997, Molecular Psychiatry.

[68]  H. Ishida,et al.  Nitric oxide reversibly suppresses xanthine oxidase activity. , 1994, Free radical research.

[69]  W. Gattaz,et al.  Increased platelet phospholipase A2 activity in schizophrenia , 1995, Schizophrenia Research.

[70]  P. Kinnunen,et al.  Increased plasma phospholipase-A2 activity in schizophrenic patients: Reduction after neuroleptic therapy , 1987, Biological Psychiatry.

[71]  Jeffrey K. Yao,et al.  Oxidative Damage and Schizophrenia , 2001, CNS drugs.

[72]  Etelvino J. H. Bechara,et al.  Activities of superoxide dismutase and glutathione peroxidase in schizophrenic and manic-depressive patients. , 1986, Clinical chemistry.

[73]  H. Hermesh,et al.  The effect of vitamin E addition to acute neuroleptic treatment on the emergence of extrapyramidal side effects in schizophrenic patients: An open label study , 1999, European Neuropsychopharmacology.