3-nitrotyrosine and Schizophrenia

The underlying mechanism of atypical antipsychotics in treating cognitive impairment in schizophrenia is unclear. The aim of the present study was to evaluate the effects of quetiapine, an atypical antipsychotic drug, on object recognition memory and hippocampal oxidative stress in a phencyclidine (PCP) rat model of schizophrenia. Rats were treated with chronic quetiapine (10 mg/kg/day, intraperitoneally) for 16 days or acute quetiapine (10 mg/kg/day, intraperitoneally) on day 16. On day 16, 1 h after the administration of quetiapine, the rats were administered PCP (50 mg/kg, subcutaneously). After the last object recognition behavioral test on day 18, the rats were killed for the measurement of hippocampal protein expression of nitrotyrosine, a protein marker of oxidative stress. The results showed that chronic quetiapine significantly attenuated object recognition memory impairment and hippocampal oxidative stress in the PCP-injected rats. These suggest that the attenuating effect of chronic quetiapine on hippocampal oxidative stress may be related to quetiapine's beneficial effects on object recognition memory in PCP rats, and further suggest that neuroprotective mechanisms are involved in chronic quetiapine treatment.

Topics: Animals; Antipsychotic Agents; Female; Hippocampus; Oxidative Stress; Phencyclidine; Quetiapine Fumarate; Rats, Sprague-Dawley; Recognition, Psychology; Schizophrenia; Schizophrenic Psychology; Tyrosine

Previously, we found decreased mitochondrial complex I subunits levels and increased protein oxidation and nitration in postmortem prefrontal cortex (PFC) from patients with bipolar disorder (BD) and schizophrenia (SCZ). The objectives of this study were to replicate our findings in an independent sample of subjects with BD, and to examine more specifically oxidative and nitrosative damage to mitochondrial and synaptosomal proteins and lipid peroxidation in myelin. We isolated mitochondria, synaptosomes, and myelin using a percoll gradient from postmortem PFC from patients with BD, SCZ, and healthy controls. Levels of mitochondrial complex I and III proteins, protein oxidation (carbonylation), and nitration (3-nitrotyrosine) were assessed using immunobloting analysis. Lipid peroxidation [lipid hydroperoxides (LPH), 8-isoprostane (8-Iso), 4-hydroxy-2-nonenal (4-HNE)] were measured using colorimetric or ELISA assays. We found decreased complex I subunits levels in BD subjects compared with control (CTL), but no difference in complex III subunits. Carbonylation was increased in synaptosomes from BD group while 3-nitrotyrosine was increased in mitochondria from BD and SCZ groups. 8-Iso was found increased in the BD group while 4-HNE was increased in both SCZ and BD when compared with controls with no differences in LPH. Our results suggest that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins. Oxidative stress has been shown to be higher in the brain of patients with bipolar disorder (BD). Here, we demonstrated increased levels of protein oxidation in synaptosomes from postmortem prefrontal cortex from patients from BD group, while 3-nitrotyrosine was increased in mitochondria from BD and schizophrenia (SCZ) groups. Moreover, lipid peroxidation was found increased in the BD when compared with controls; suggesting that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins.

Topics: Bipolar Disorder; Case-Control Studies; Electron Transport Complex I; Electron Transport Complex III; Female; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Humans; Lipid Peroxidation; Male; Middle Aged; Mitochondria; Oxidation-Reduction; Oxidative Stress; Prefrontal Cortex; Schizophrenia; Superoxide Dismutase; Synaptosomes; Tyrosine

The psychotomimetic effects of N-methyl-D-aspartate (NMDA) receptor antagonists in healthy humans and their tendency to aggravate psychotic symptoms in schizophrenic patients have promoted the notion of altered glutamatergic neurotransmission in the pathogenesis of schizophrenia.. The NMDA-receptor antagonist MK-801 was chronically administered to rats (0.02 mg/kg intraperitoneally for 14 days). In one subgroup the antipsychotic haloperidol (1 mg/kg) was employed as a rescue therapy. Glutamate distribution and 3-NT (3-nitrotyrosine) as a marker of oxidative stress were assessed by immunohistochemistry in tissue sections. In parallel, the effects of MK-801 and haloperidol were investigated in primary embryonal hippocampal cell cultures from rats.. Chronic NMDA-R antagonism led to a marked increase of intracellular glutamate in the hippocampus (126.1 +/- 10.4% S.E.M of control; p=0.037), while 3-NT staining intensity remained unaltered. No differences were observed in extrahippocampal brain regions. Essentially these findings could be reproduced in vitro.. The combined in vivo and in vitro strategy allowed us to assess the implications of disturbed glutamate metabolism for the occurrence of oxidative stress and to investigate the effects of antipsychotics. Our data suggest that oxidative stress plays a minor role in this model than previously suggested. The same applies to apoptosis. Moreover, the effect of haloperidol seems to be mediated through yet unidentified mechanisms, unrelated to D2-antagonism. These convergent lines of evidence indicate that further research should be focused on the glutamatergic system and that our animal model may provide a tool to explore the biology of schizophrenia.

Topics: Animals; Antipsychotic Agents; Cells, Cultured; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Haloperidol; Hippocampus; Male; Oxidative Stress; Rats; Rats, Long-Evans; Reactive Oxygen Species; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Tyrosine

Accumulating evidence suggests that mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of bipolar disorder and schizophrenia. It remains unclear whether mitochondrial dysfunction, specifically complex I impairment, is associated with increased oxidative damage and, if so, whether this relationship is specific to bipolar disorder.. To evaluate whether decreased levels of the electron transport chain complex I subunit NDUFS7 are associated with complex I activity and increased oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder, schizophrenia, or major depressive disorder.. Postmortem prefrontal cortex from patients and controls were assessed using immunoblotting, spectrophotometric, competitive enzyme immunoassay to identify group differences in expression and activity of complex I, and in oxidative damage in mitochondria.. University of British Columbia, Vancouver, Canada. Patients Forty-five patients with a psychiatric disorder (15 each with bipolar disorder, schizophrenia, and major depressive disorder) and 15 nonpsychiatric control subjects were studied.. Oxidative damage to proteins and mitochondrial complex I activity.. Levels of NDUFS7 and complex I activity were decreased significantly in patients with bipolar disorder but were unchanged in those with depression and schizophrenia compared with controls. Protein oxidation, as measured by protein carbonylation, was increased significantly in the bipolar group but not in the depressed or schizophrenic groups compared with controls. We observed increased levels of 3-nitrotyrosine in the bipolar disorder and schizophrenia groups.. Impairment of complex I may be associated with increased protein oxidation and nitration in the prefrontal cortex of patients with bipolar disorder. Therefore, complex I activity and mitochondrial dysfunction may be potential therapeutic targets for bipolar disorder.

Topics: Adult; Aged; Antipsychotic Agents; Bipolar Disorder; Depressive Disorder, Major; Electron Transport Complex I; Female; Humans; Male; Middle Aged; Mitochondrial Proteins; NADH Dehydrogenase; Oxidative Stress; Prefrontal Cortex; Schizophrenia; Tyrosine

The level of various specific biomarkers of oxidative stress in plasma from schizophrenic patients, as well as biomarkers (the level of isoprostanes) in urine in schizophrenic patients was described. The aim of our present study was to evaluate biomarkers of oxidative stress by oxidative/nitrative modifications of plasma proteins (by measuring the level of carbonyl groups and 3-nitrotyrosine in proteins) from patients with schizophrenic disorders and from control group. We also investigated the level of low-molecular-weight thiols [glutathione (GSH), cysteine (CSH), cysteinylglycine (CGSH) and homocysteine] in plasma obtained from schizophrenic patients and from healthy volunteers. Patients hospitalized in the 1st and 2nd Psychiatric Department of the Medical University in Lodz, Poland were interviewed with a special questionnaire (treatment, course of diseases, dyskinesis and other extrapyramidal syndromes). According to DSM-IV criteria, all patients had a diagnosis of paranoid type. They were treated with antipsychotic drugs (clozapine, risperidone, olanzapine). The mean duration of schizophrenia was about 5 years.. Levels of carbonyl groups and 3-nitrotyrosine residues in plasma proteins were measured by ELISA and a competition ELISA, respectively. High-performance liquid chromatography was used to analyze free thiols in plasma.. We observed a statistically increased level of biomarkers of oxidative/nitrative stress such as carbonyl groups or 3-nitrotyrosine in plasma proteins from schizophrenic patients. In schizophrenic patients the amount of homocysteine in plasma was higher compared with the control group; the level of GSH, CSH and CGSH was decreased. This indicates that reactive oxygen species and reactive nitrogen species may stimulate oxidative/nitrative modifications of plasma proteins in schizophrenic patients.. Considering the data presented in this study, we suggest that the amount of carbonyl groups and 3-nitrotyrosine in plasma proteins may be important indicators of protein damage in vivo in schizophrenia.

Topics: Adult; Biomarkers; Blood Proteins; Chromatography, High Pressure Liquid; Cysteine; Dipeptides; Enzyme-Linked Immunosorbent Assay; Female; Glutathione; Homocysteine; Humans; Male; Oxidative Stress; Schizophrenia; Tyrosine

Oxidative damage to lipids in plasma, blood platelets and neurons in patients with schizophrenia was described. The aim of our present study was to evaluate oxidative/nitrative modifications of blood platelets proteins by measurement the level of biomarkers of oxidative stress such as carbonyl groups, thiol groups and 3-nitrotyrosine in proteins in patients with schizophrenia and compare with a control group. Levels of carbonyl groups and 3-nitrotyrosine residues in platelet proteins were measured by ELISA and competition ELISA, respectively. The method with 5,5'-dithio-bis(2-nitro-benzoic acid) has been used to analyse thiol groups in platelet proteins. We demonstrated for the first time in platelet proteins from patients with schizophrenia a statistically significant increase of the level of biomarkers of oxidative/nitrative stress such as carbonyl groups or 3-nitrotyrosine; in schizophrenic patients the amount of thiol groups in platelet proteins was lower than in platelets from healthy subjects. Our results strongly indicate that in patients with schizophrenia reactive oxygen species and reactive nitrogen species induce not only peroxidation of lipids, but also may stimulate oxidative/nitrative modifications of platelet proteins. The consequence of these modifications may be the alteration of platelet protein structure and function.

Topics: Adult; Blood Platelets; Blood Proteins; Female; Humans; Male; Oxidation-Reduction; Oxidative Stress; Protein Carbonylation; Reactive Nitrogen Species; Reactive Oxygen Species; Schizophrenia; Surveys and Questionnaires; Tyrosine