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 tha t has been correlated with age-related increases in the central nervou s system activity of the enzyme responsible for its bioactivation, mon oamine oxidase type B (MAO B). To characterize the involvement of MAO B further in the age-related effects of MPTP, a neurotoxic analog of M PTP, hyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP), was used. This drug produced much larger depletions of striatal dopami ne in 10-month-old mice than in 2-month-old animals, which indicated t hat the effects of 2'CH3-MPTP, like those of MPTP, are age related. Di fferent from MPTP, however, neither the inhibition of MAO B (selegilin e) nor MAO A (clorgiline) blocked the dopamine-depleting effects of 2' CH3-MPTP; rather, the simultaneous inhibition of both forms of the enz yme was required. These data indicate that both MAO A and B participat e in the bioactivation of 2'CH3-MPTP. Based on these findings, the abi lity of selective inhibitors of MAO A and B to block the age-related e ffects of 2'CH3-MPTP was investigated. 2'CH3-MPTP produced equivalent depletions of striatal dopamine in 2- and 10-month-mice after both gro ups 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-induc ed depletions of striatal dopamine than did younger rodents after the inhibition of MAO A. The findings suggest that the age-dependent dopam ine-depleting effects of 2'CH3-MPTP occur as a consequence of age-rela ted increases in central nervous system MAO B activity.