Potentiation of MPTP by 4-phenylpyridine on the neuromuscular blockade in mouse phrenic nerve-diaphragm

Potentiation by 4-phenylpyridine (a MAO-B Inhibitor) on the neuromuscular blocking action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied in mouse phrenic nerve-diaphragm. MPTP blocked nerve-evoked twitches in a concentration (1-200 microM)-dependent manner. 4-Phenylpyridine, but not pargyline or tranylcypromine potentiated this inhibitory effect of MPTP. Pretreatment with 50 microM 4-phenylpyridine, reduced IC50 (concentration for 50% inhibition of twitch amplitude) values of MPTP from 53 to 18 microM and d-tubocurarine from 0.7 to 0.3 microM, respectively. 4-Phenylpyridine also enhanced the inhibitory action of MPTP and d-tubocurarine on acetylcholine (0.1 mM)-induced contracture of the denervated mouse diaphragm. The twitch inhibition induced by alpha-bungarotoxin and the specific binding of [125I]alpha-bungarotoxin to the mouse diaphragm were potentiated by 4-phenylpyridine but the inhibitory action of MPTP and d-tubocurarine on [125I]alpha-bungarotoxin binding were not significantly changed by pretreatment with 4-phenylpyridine. Electrophysiological studies revealed that the inhibitory actions of MPTP and d-tubocurarine on the amplitudes of m.e.p.ps and e.p.ps were augmented by 4-phenylpyridine. These indicate that 4-phenylpyridine enhanced the neuromuscular blocking action of the MPTP and d-tubocurarine at the postsynaptic nicotinic acetylcholine receptors. The implication of this finding is that the possible application of 4-phenylpyridine in the MPTP-induced Parkinson's disease is limited by its potentiation on the neuromuscular blocking action of MPTP.