Biochemical and pharmacological studies of transmethylation mechanisms in the central nervous system

Abstract: Transmethylation is a biochemical process that involves the transfer of a methyl group from a donor to an acceptor compound. Transmethylation reactions are involved in the biosynthesis of nucleic acids, proteins,phospholipids and catecholamines and are therefore essential for the survival of all living organisms. Central to these reactions is the methyl donor S-adenosylmethionine (SAM) which is synthesized through enzymatic action of L-methionine adenosylransferase (ATP:L-methionine S-adenosyltransferase, E C 2.5.1.6, MAT). In recent years, a number of studies have linked defects in transmethylation with mental illnesses like schizophrenia, Alzheimer's disease and Parkinson's disease. There is presently no preventive or curative medication available for these neuropsychiatric disorders. In this study experiments were conducted on laboratory animals and human samples in an attempt to associate defects in transmethylation mechanisms that could underlie diseases such as schizophrenia and subacute myelo-optic neuropathy (SMON). Both histological and biochemical analyses of enzymes and substrates involved in transmethylation reactions were carried out. In schizophrenic patients, MAT activity was decreased in erythrocytes and kinetic properties were altered in the brain. Most patients in the present studies were, however, on neuroleptic therapy. MAT activity was decreased in brain of methamphetamine but not PCP-treated rats. The MAT activity was significantly increased after haloperidol treatment but not afterclozapine. Tolcapone and phenelzine, inhibitors of catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO), respectively, are used as adjuvant to L-dopa therapy in Parkinson's disease. Rats treated with tolcapone were found to have increased SAM levels while those treated with phenelzine had decreased SAM levels.To further understand the mechanisms of the chelating agent clioquinol which caused the disaster called SMON, mice were treated with clioquinol. Acute treatment resulted in increased SAM levels in the brain. On the other hand, chronic treatment caused a reduction of vitamin B12 uptake and trace metal concentrations in the brain. Clioquinol-induced brain damage might therefore arise from decreased vitamin B12 uptake in the brain, which might be of relevance for the development of SMON. Taken together, these data suggest that there is a close association between transmethylation reactions and a variety of neuropsychiatric diseases. These associations should be of interest both from an etiological and pharmacotherapeutic point of view.