Age-dependent effects of the 2'-methyl analog of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine: prevention by inhibitors of monoamine oxidase B.
Older mice are much more susceptible to the dopamine-depleting actions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an effect that has been correlated with age-related increases in the central nervous system activity of the enzyme responsible for its bioactivation, monoamine oxidase type B (MAO B). To characterize the involvement of MAO B further in the age-related effects of MPTP, a neurotoxic analog of MPTP, 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP), was used. This drug produced much larger depletions of striatal dopamine in 10-month-old mice than in 2-month-old animals, which indicated that the effects of 2'CH3-MPTP, like those of MPTP, are age related. Different from MPTP, however, neither the inhibition of MAO B (selegiline) nor MAO A (clorgiline) blocked the dopamine-depleting effects of 2'CH3-MPTP; rather, the simultaneous inhibition of both forms of the enzyme was required. These data indicate that both MAO A and B participate in the bioactivation of 2'CH3-MPTP. Based on these findings, the ability of selective inhibitors of MAO A and B to block the age-related effects of 2'CH3-MPTP was investigated. 2'CH3-MPTP produced equivalent depletions of striatal dopamine in 2- and 10-month-mice after both groups were pretreated with selective inhibitors of MAO B; that is, MAO B inhibition abolished the age-dependent effects of the neurotoxin. By contrast, older mice continued to display much larger 2'CH3-MPTP-induced depletions of striatal dopamine than did younger rodents after the inhibition of MAO A.(ABSTRACT TRUNCATED AT 250 WORDS)
Finnegan
K T
KT
Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, USA.
Irwin
I
I
Delanney
L E
LE
Langston
J W
JW
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000375:Aging / Q000378:metabolism*; D000818:Animals; D003010:Clorgyline / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D012642:Selegiline / Q000494:pharmacology*
D008996:Monoamine Oxidase Inhibitors; D012642:Selegiline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D003010:Clorgyline; D004298:Dopamine