Effect of highly halogenated beta-carbolines on dopaminergic cells in culture and on mitochondrial respiration

Pyridoindoles (carbolines) are relatively common indole alkaloids in most d iets and in our ecosystem. Besides 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri dine (MPTP) and its active metabolite, MPP+, several psychotropic beta-carb olines have been described to exhibit neurotoxic effects on the dopaminergi c system. In this work, we have investigated a new class of neurotoxic P-ca rbolines, the highly halogenated tetrahydro-beta-carbolines. The present co mpounds are derived from the condensation of endogenous tryptamine with the hypnotic drug chloral hydrate or by exposure to the industrial solvent tri chloroethylene (which can be metabolized to chloral). These tetrahydro-beta -carbolines inhibit the mitochondrial respiratory chain, acting as strong i nhibitors of Complex I and partial inhibitors of Complex II. They are also neurotoxic to dopaminergic neurons in primary cell culture. (C) 1999 Wiley- Liss, Inc.