1,2,3,6-Tetrahydro-1-methyl-4-(methylpyrrol-2-yl)pyridine: studies on the mechanism of action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

K. T. Finnegan, I. Irwin, L. E. Delanney, G. A. Ricaurte, J. W. Langston

Research output: Contribution to journalArticle

Abstract

Two analogs of the nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were examined for their deleterious effects on nigrostriatal neurons. 1,2,3,6-Tetrahydro-1-methyl-4-(methylpyrrol-2-yl)pyridine (TMMP), but not 1-methyl-4-(1-methylpyrrol-2-yl)-4-piperidinol, caused persistent depletion of striatal dopamine and induced histologic evidence of nerve terminal degeneration in mice. These findings differ diametrically from results previously reported for the two analogs. TMMP produced larger dopamine depletions than MPTP when the two drugs were given in equivalent doses. Further experiments demonstrated that TMMP is preferentially oxidized by mouse brain monoamine oxidase B to water-soluble compound, most likely the pyridinium ion species. Prior treatment of mice with either the monoamine oxidase inhibitor pargyline or the dopamine reuptake inhibitor bupropion blocked the ability of TMMP to deplete striatal dopamine. Thus, the pharmacologic profile of TMMP closely resembles that of MPTP. That TMMP and MPTP induce dopamine depletions by a similar mechanism tends to support the proposed neurochemical sequence of events thought to lead to the expression of MPTP-induced neurotoxicity. The authors' observations provide further evidence that MPTP is not unique in its capability to damage nigrostriatal neurons.

Original languageEnglish (US)
Pages (from-to)1144-1151
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume242
Issue number3
StatePublished - Dec 1 1987

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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