Abstract

Parkinson's disease (PD) is believed to be induced by the interaction of genetic predisposition and environmental factors, and a type of neurotoxin is proposed to be one of the environmental factors. We designed and synthesized a molecule, 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) as a possible PD-eliciting neurotoxin and evaluated its characteristics relevant to PD. 1BnTIQ is an endogenous amine in the brain and the 1BnTIQ content increases in the patients with PD. Repeated administration of 1BnTIQ induced PD-like symptoms in monkeys and mice. 1BnTIQ was biosynthesized from 2-phenylethylamine and phenylacetaldehyde, which is a metabolite of 2-phenylethylamine, and used in in vivo and in vitro studies. 1BnTIQ inhibited [3H] dopamine uptake in HEK293 cells which stably express dopamine transporter. 1BnTIQ also inhibited NADH-ubiquinone oxidoreductase (complex I) in the mitochondrial respiratory chain. Next, we assessed 1BnTIQ neurotoxicity in the organotypic coculture of the ventromedial portion of the mesencephalon and striatum. 1BnTIQ decreased the dopamine content in the mesencephalon in both dose- and time-dependent manners and it irreversibly reduced the dopamine content. Furthermore, it caused morphological changes in tyrosine hydroxylase-positive cells in the mesencephalon and reduced the number of cells. 1-(3',4'-Dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3'4'DHBnTIQ) is also an endogenous parkinsonism-inducing 1BnTIQ derivative. In vivo and in vitro studies revealed that 3'4'DHBnTIQ was O-methylated by soluble catechol-O-methyltransferase (COMT). The result that COMT inhibitor suppressed 3'4'DHBnTIQ neurotoxicity suggests that 3'4'DHBnTIQ is metabolically activated by COMT to exert toxic effects.