DEPRENYL ANTAGONIZES ACUTE LETHALITY OF 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE IN MICE

  • 1 November 1988
    • journal article
    • research article
    • Vol. 247  (2) , 531-535
Abstract
In Charles River CFW mice, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused lethality with an LD50 of 53.8 mg/kg s.c. In mice pretreated with deprenyl, no lethality occurred with MPTP doses up to 110 mg/kg s.c. MPTP alone at doses of 30 to 90 mg/kg s.c. caused marked salivation, licking and grooming, hyperlocomotion, hyperreactivity and convulsions during the 1st hr, followed by depression, continued salivation and respiratory distress at 2 to 3 hr and at longer times, with death occurring at the higher doses. In deprenyl-pretreated mice, MPTP produced only mild and transient effects. 1-Methyl-4-phenylpyridinium (MPP+) was more potent in causing lethality than was MPTP, and deprenyl did not affect its lethality. MPTP lethality was not antagonized by EXP 561 [4-phenyl-bicyclo-(2,2,2)octan-1-amine hydrochloride monohydrate], an uptake inhibitor that prevented the neurotoxic effects of a lower dose of MPTP on striatal dopamine and cortical norepinephrine neurons. In addition to deprenyl, other monoamine oxidase (MAO) inhibitors effective in inhibiting MAO-B (MD 240928 {R-3-[4-((3-chlorophenyl)methoxy)phenyl]-5-[(methylamino)methyl]-2-oxazolidinone methanesulfonate} and pargyline) protected against MPTP-induced lethality, but LY 51641 {N-[2-(o-chlorophenoxy)ethyl]cyclopropylamine hydrochloride} (a selective inhibitor of MAO-A) did not. The protective effect of deprenyl against MPTP-induced lethality was dose-dependent over a dose range of 0.01 to 10 mg/kg; in this range deprenyl inhibited MAO type B (MAO-B) in brain and liver. A 10-mg/kg i.p. dose of deprenyl antagonized MPTP-induced lethality as long as 14 days. MAO-B activity in brain was inhibited throughout this period, but MAO-B activity in liver recovered within 3 days. The protective effect of deprenyl thus related to its inhibition of MAO-B in brain. Deprenyl pretreatment markedly reduced MPP+ concentrations in brain after MPTP injection, without altering MPTP concentrations in brain. These findings suggest that a metabolite of MPTP, probably MPP+, previously implicated in the catecholamine-depleting effects of lower doses of MPTP, accounts for the lethality of higher doses of MPTP in mice.