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Indole-N-methylated beta-carbolinium ions as potential brain-bioactivated neurotoxins
M A Collins1, E J Neafsey, K Matsubara
1Department of Molecular and Cellular Biochemistry, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153.
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 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.
Insights
New research suggests that certain beta-carbolines, when methylated in the brain, can become potent neurotoxins. These compounds may contribute to Parkinson's disease development by damaging dopaminergic neurons.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- N-Methyl-4-phenylpyridinium ion (MPP+) is a neurotoxin linked to Parkinson's disease, selectively targeting dopaminergic neurons.
- Endogenous or activated agents resembling MPP+ are hypothesized to play a role in Parkinson's disease pathogenesis.
Purpose of the Study:
- To investigate the neurotoxic potential of methylated beta-carbolines.
- To explore the role of endogenous beta-carbolines in Parkinson's disease.
Main Methods:
- In vitro studies using PC12 cell cultures to assess mitochondrial inhibition and neurotoxicity.
- In vivo studies involving striatal microdialysis in animal models.
- Analysis of S-adenosylmethionine-dependent methylation of beta-carbolines by brain enzymes.
Main Results:
- Specifically methyl-substituted beta-carbolines exhibited mitochondrial inhibitory and neurotoxic effects comparable to or exceeding MPP+.
- Brain enzymes catalyze the di-N-methylation of beta-carbolines, forming toxic 2,9-N,N'-dimethyl-beta-carbolinium ions.
- The 9-indole-N-methyl transfer, a novel finding in animals, requires prior 2-beta-nitrogen methylation.
Conclusions:
- Sequential di-N-methylation of beta-carbolines represents a potential brain bioactivation pathway for neurotoxin formation.
- These findings suggest that endogenous or xenobiotic beta-carbolines may contribute to neurodegeneration in conditions like Parkinson's disease.