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Deprenyl antagonizes acute lethality of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine in mice

RW Fuller, SK Hemrick-Luecke and KW Perry

Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 247, Issue 2, pp. 531-535, 11/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


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 J. Pharmacol. Exp. Ther.Home page
E. L. Unger, P. Mazzola-Pomietto, D. L. Murphy, and A. M. Andrews
2'-NH2-MPTP [1-Methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine] Depletes Serotonin and Norepinephrine in Rats: A Comparison with 2'-CH3-MPTP [1-Methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine]
J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 527 - 533.
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