Striatal dopaminergic toxicity following intranigral injection in rats of 2-methyl-norharman, a beta-carbolinium analog of N-methyl-4-phenylpyridinium ion (MPP+).

Methylated beta-carboline compounds are mammalian indole metabolites that we have proposed to be endogenous neurotoxins due to their structural similarity to MPP+, the active oxidized product of the dopaminergic toxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Several laboratories have demonstrated that MPP+ administration into the substantia nigra or median forebrain bundle of rats results in extensive depletion of striatal dopamine and its metabolites. We now report that three weeks after intranigral injection of the beta-carboline, 2-methyl-norharman, striatal dopamine, DOPAC, and homovanillic acid (HVA) concentrations ipsilateral to the injection are reduced 41-64% compared to vehicle-injected controls; in individual animals dopamine depletions of 96% were achieved. In addition, at the 2-methyl-norharman injection site in the substantia nigra, large lesions and gliosis were apparent under light microscopic examination. This is the first direct demonstration that a 2-methyl-beta-carbolinium ion is neurotoxic. It lends further validity to the hypothesis that MPP+-like beta-carbolines may be endogenous causative agents in Parkinson's disease.