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

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 NADH-ubiquinone 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.