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.