Deprenyl antagonizes acute lethality of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.
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)
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D001921:Brain / Q000201:enzymology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007527:Isoenzymes / Q000378:metabolism; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology*; D011725:Pyridines / Q000633:toxicity*; D011726:Pyridinium Compounds / Q000494:pharmacology; D012472:Salivation / Q000187:drug effects; D012642:Selegiline / Q000494:pharmacology*
D001643:Bridged Bicyclo Compounds; D003521:Cyclopropanes; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D010627:Phenethylamines; D011725:Pyridines; D011726:Pyridinium Compounds; C013358:EXP561; D012642:Selegiline; C000434:Lilly 51641; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D015655:1-Methyl-4-phenylpyridinium