Indole-N-methylated β-carbolinium ions as potential brain-bioactivated neurotoxins

Abstract N -Methyl-4-phenylpyridinium ion (MPP + ), a highly toxic metabolite produced in the brain from a street drug contaminant, is selectively taken up by nigrostriatal dopaminergic neurons and accumulated intraneuronally in mitochondria. There it inhibits respiration, causes neuronal death and, in primates, provokes a parkinsonian condition. It has been suggested that endogenously generated or activated agents resembling MPP + may contribute to the development of Parkinson's disease. We report here that simple β-carbolines derived from tryptophan or related open chain indoles, when specifically methyl-substituted on both (2[β] and 9[indole]) available nitrogens, display mitochondrial inhibitory potencies and neurotoxic effects in vitro (PC12 cultures) and in vivo (striatal microdialysis) which approach or even surpass MPP + . These results take on physiological significance with our finding that brain enzyme activity catalyzes S -adenosylmethionine-dependent methylations of the β- and indole-nitrogens in β-carbolines that have been detected in vivo. The unusual 9[indole]- N -methyl transfer, previously unrecognized in animals, apparently requires prior methylation of the 2[β]-nitrogen. Sequential di- N -methylation of endogenous or xenobiotic β-carbolines to form unique, neurotoxic 2, 9- N , N′-dimethyl-β-carbolinium ions may serve as a brain bioactivation route in chronic neurodegenerative conditions such as Parkinson's disease.