PMID: 2481322Jan 1, 1989Paper

Neurotoxic properties of a serotonin oxidation product: possible role in Alzheimer's disease.

Progress in Clinical and Biological Research
L VolicerN Wolfe

Abstract

Properties of a partially oxidized form of serotonin (5-HT), 4,5-diketotryptamine (4,5-DKT), synthesized by electrochemical oxidation of 5-HT, were investigated. Administration of 4,5-DKT into the lateral ventricles (i.c.v.) of rats resulted in cell death and terminal degeneration in entorhinal, insular, and posterior cingulate cortices, and in the CA1, CA3 and dentate gyrus sectors of hippocampus. Furthermore, i.c.v. administration of 4,5-DKT resulted in a significant depletion of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in prefrontal cortex, striatum and hippocampus. 4,5-DKT injection into cingulate and hippocampal cortices resulted in cell death and terminal degeneration in these structures. In brain fragment perfusion and incubation experiments, 4,5-DKT increased dose dependently 5-HT efflux from rat hippocampus and striatum. The efflux of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid from striatum was unaffected. In hippocampal preparations, fluoxetine decreased 4,5-DKT-stimulated efflux of 5-HT by 24%, and pargyline did not affect it. In vitro, 4,5-DKT bound covalently to nucleophilic -SH groups in glutathione and mercaptoethanol and the binding was blocked by N-ethyl-maleimide. 4,5-DKT bound selec...Continue Reading

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