Isoquinoline neurotoxins in the brain and Parkinson's disease

Parkinson's disease is thought to be caused by some unknown endogenous or exogenous factors interacting with genetic dispositions. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an exogenous neurotoxin producing parkinsonism in humans, monkeys and various animals as the result of monoamine oxidase type B (MAO-B)-catalyzed conversion of it to the 1-methyl-4-phenyl-pyridinium ion (MPP+), which selectively kills the nigrostriatal dopaminergic neurons. Various isoquinoline derivatives were found in the brain of patients with Parkinson's disease. Isoquinoline derivatives have neurochemical properties similar to those of MPTP and they are considered to be the endogenous neurotoxins which cause Parkinson's disease. Among them, tetrahydroisoquinoline (TIQ), 1-benzyl-TIQ, and (R)-1,2-dimethyl-5,6-dihydroxy-TIQ [(R)-N-methyl-salsolinol)] have the most potent neurotoxicity. TIQs, like MPTP, may be activated via N-methylation by N-methyltransferase and oxidation by MAO. TIQs as well as MPP+ inhibit complex I of the electron transport system in mitochondria, thereby reducing ATP formation and producing oxygen radicals. Although the properties of TIQs are similar to those of MPTP, the neurotoxicity of TIQs is weaker than that of MPTP. Since Parkinson's disease is a slowly progressing neurodegenerative disease, long term neurotoxic effects of IQs remain to be further examined in primates.