Characteristics of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the mouse.
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 substrate for monoamine oxidase than was MPTP (Km values of 66 and 114 microM and Vmax 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 Km and Vmax 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 (mazindol 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.(ABSTRACT TRUNCATED AT 250 WORDS)
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D010084:Oxidation-Reduction; D011725:Pyridines / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D008996:Monoamine Oxidase Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D011725:Pyridines; C048977:1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine