Abstract
MPTP-3-ol injected s.c. once daily for 4 days resulted in a dose-dependent depletion of striatal dopamine and cortical norepinephrine one week after the last dose. MPTP-3-ol was approximately one-fourth as potent as MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in causing these effects. MPTP-3-ol was oxidized by monoamine oxidase in mouse brain in vitro and resulted in MPP+ (1-methyl-4-phenylpyridinium) formation in brain in vivo , both at about one-fourth the rates with MPTP. The in vitro metabolism of MPTP-3-ol was inhibited by deprenyl, a selective inhibitor of monoamine oxidase type B, and deprenyl pretreatment also blocked the depletion of striatal dopamine and cortical norepinephrine in vivo . Pretreatment with EXP 561, an inhibitor of catecholamine uptake, also prevented the dopamine- and norepinephrine-depleting effects of MPTP-3-ol. Thus, substitution of a hydroxy group on the 3-position of MPTP retains its neurotoxic potential toward catecholamine neurons but reduces potency by decreasing the rate of oxidation via monoamine oxidase type B.
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