Indole-N-methylated beta-carbolinium ions as potential brain-bioactivated neurotoxins.
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 beta-carbolines derived from tryptophan or related open chain indoles, when specifically methyl-substituted on both (2[beta] 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 beta- and indole-nitrogens in beta-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[beta]-nitrogen. Sequential di-N-methylation of endogenous or xenobiotic beta-carbolines to form unique, neurotoxic 2,9-N,N'-dimethyl-beta-carbolinium ions may serve as a brain bioactivation route in chronic neurodegenerative conditions such as Parkinson's disease.
Collins
M A
MA
Department of Molecular and Cellular Biochemistry, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153.
Neafsey
E J
EJ
Matsubara
K
K
Cobuzzi
R J
RJ
Rollema
H
H
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors; D000818:Animals; D001711:Biotransformation / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002243:Carbolines / Q000493:pharmacokinetics* / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects; D005260:Female; D008745:Methylation; D008928:Mitochondria / Q000187:drug effects; D015394:Molecular Structure; D009243:NAD / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D016716:PC12 Cells; D051381:Rats; D011919:Rats, Inbred Strains; D012436:S-Adenosylmethionine / Q000502:physiology*
D002243:Carbolines; D009243:NAD; D000244:Adenosine Diphosphate; D012436:S-Adenosylmethionine