Characteristics of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the mouse

S. K. Youngster, M. V. Kindt, R. E. Heikkila

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57 Scopus citations


1-Methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP) was shown previously to be a more potent neurotoxicant than 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. The present investigation was conducted to determine possible reasons for the greater potency of 2'CH3-MPTP and to determine if its neurotoxic action might be similar to that of MPTP. 2'CH3-MPTP was a much better subtrate for mono-amine oxidase than was MPTP (K(m) values of 66 and 114 μM and V(max) values of 3433 and 1389 nmol/g of tissue per hr for 2'CH3-MPTP and MPTP, respectively) and it is likely that this is an important feature which contributes to its greater potency. In addition, its pyridinium metabolite, 1-methyl-4-(2'-methylphenyl)pyridinium was found to be an excellent substrate for the dopamine carrier with K(m) and V(max) values (513 nM and 4.1 nmol/g of tissue per min, respectively) similar to those of 1-methyl-4-phenylpyridinium (872 nM and 5.2 nmol/g of tissue per min, respectively). In vivo, 2'CH3-MPTP-induced neurotoxicity, like MPTP-induced neurotoxicity, was attenuated by the pretreatment of mice with a dopamine uptake inhibitor (maxindol or GBR 13069). However, selective doses of the monoamine oxidase (MAO)-B inhibitors, deprenyl or MDL 72145, failed to prevent in vivo neurotoxicity induced by 2'CH3-MPTP although these doses effectively blocked MPTP-induced neurotoxicity. Protection against 2'CH3-MPTP-induced neurotoxicity was observed only at a nonselective dose of MDL 72145 which blocked both MAO-B and MAO-A activities. Both in vitro and ex vivo experiments demonstrate a small, but apparently important, role for MAO-A in the oxidation of 2'CH3-MPTP. All of this demonstrates that there are many similarities, but also some important differences, between the neurotoxic actions of 2'CH3-MPTP and MPTP.

Original languageAmerican English
Pages (from-to)850-857
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - 1987

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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