Superoxide, neuroleptics and the ubiquinone and cytochrome b5 reductases in brain and lymphocytes from normals and schizophrenic patients

Abstract

The effects of the neuroleptic flupenthixol on the expression of the genes coding for the mitochondrial ubiquinone and cytochrome b 5 reductases have been studied because of the importance of these enzymes in energy metabolism, oxidative stress and also because similar but oppositely directed changes have been previously observed in the cerebral cortex from schizophrenics. The neuroleptic flupenthixol reduces the expression in rats of the gene coding for NADH-cytochrome b 5 reductase as measured by in situ hybridisation and its enzymic manifestation. Flupenthixol also reduces the enzymic activity of the mitochondrial NADHubiquinone reductase, and it has been previously shown that mRNA from the mitochondrially coded parts of the enzyme are reduced by the drug. Both the cis-and therapeutically less active trans-flupenthixol were found to produce these changes in rats. Post-mortem brain tissue from schizophrenics who have received neuroleptic medication have reduced levels of both reductases as measured enzymically, Lymphocyte samples from schizophrenics also have reduced levels of both reductases compared with normals. The superoxide anion O − 2 is the principle agent of oxidative stress and both the cytochrome b 5 and the ubiquinone reductase enzymes were semi-purified from sheep liver and shown to produce appreciable amounts of superoxide. Superoxide production is reduced in brain homogenates from rats treated with flupenthixol. Its production is also reduced in brain tissue and lymphocytes from schizophrenics receiving neuroleptic medication. We conclude that neuroleptic medication reduces the expression of both the ubiquinone and cytochrome b 5 reductase and among the effects of this reduction is a decrease in the production of neurotoxic superoxide.

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

“…[31][32][33][85][86][87][88] The results of this study extend this abnormality to bipolar disorder, whereby almost half of all significantly differentially expressed proteins identified were found to have a mitochondrial or other metabolic function. In the schizophrenia group, this figure was a quarter, suggesting that metabolic dysfunction in this area is relatively more prominent in bipolar disorder than schizophrenia.…”

The other, forgotten genome: mitochondrial DNA and mental disorders

“…However, these two lines of study are not consistent with each other since activity of complex IV was unchanged 63 or decreased 64 in the frontal lobes, while mRNA expression of complex IV increased in the frontal lobes, 62 putamen, 67 and nucleus accumbens 67 and decreased in the caudate. 67 Furthermore, antipsychotics decreased COII expression, while increasing COX activity.…”

“…Of these, increased levels of COII mRNA were confirmed in the frontal cortex of eight schizophrenic patients and five controls. 62 Increased COII was even more prominent in two drug-free schizophrenic patients, and the antipsychotic drug flupenthixol was found to decrease COII expression in experimental animals, suggesting that it was not drug-related. However, contrary to expectation, the activity of cytochrome c oxidase in the frontal cortex of patients with schizophrenia post-mortem did not show any alteration.…”

State-dependent alterations in mitochondrial complex I activity in platelets: a potential peripheral marker for schizophrenia

“…Thus, compared to healthy controls, complex I activity was significantly increased in patients in acute relapse and patients in a chronic active state but reduced in patients with residual schizophrenia. Reduced activities of complexes I and I-III have been previously reported in platelets and lymphocytes of chronic schizophrenic patients as compared with controls 14,17 and have been attributed to an inhibitory effect of antipsychotic drugs. [17][18][19][20] Indeed, a number of studies, including our own, have shown that antipsychotics inhibit complex I activity after chronic administration to rat or after in vitro addition to disrupted mitochondria.…”

“…The etiology of schizophrenia is still unknown but recent advances in neuroscience have suggested a wide array of competing mechanisms that may be involved in the disorder, [3][4][5][6] among them altered cerebral energy metabolism 7 and mitochondria dysfunction. [8][9][10][11][12][13][14] Recently, we have shown that platelet mitochondrial complex I, which is the first complex of the mitochondrial electron transport system, is significantly increased in schizophrenic patients in the acute state, and not in patients with affective disorders. 15 In the present study we further demonstrate that complex I activity is altered with disease state presenting high specificity and sensitivity.…”