Studies on the neuromuscular blocking action of MPTP in the mouse phrenic nerve-diaphragm

The peripheral neurotoxicity of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) in the mouse phrenic nerve-diaphragm preparation was studied. The inhibition of nerve-evoked twitches was dependent on the concentrations of MPTP, ranging from 1 to 200 microM, which only slightly increased the amplitude of the twitch evoked by direct stimulation of the muscle. Pretreatment with pargyline did not prevent this inhibitory action of MPTP. The inhibition of the twitch by MPTP was reversible and could be partially reversed by anticholinesterase agents such as neostigmine and physostigmine, as well as ecothiophate. Pretreatment with either 0.7 microM d-tubocurarine or 2.2 microM succinylcholine, did not affect the twitches individually but markedly potentiated the effects of MPTP, by shifting the concentration-inhibition curve of MPTP to the left. MPTP not only directly inhibited acetylcholine (0.1 mM)-induced contracture of the denervated mouse diaphragm but also protected the muscle from the inhibitory action of alpha-bungarotoxin. Furthermore, the specific binding of [125I]alpha-bungarotoxin to the mouse diaphragm was also inhibited by MPTP. Electrophysiological studies revealed that MPTP inhibited the frequency and amplitude of the m.e.p.p., as well as the amplitude of the e.p.p. All of these findings indicate that MPTP exerts a neuromuscular blocking action through a curare-like action, by binding to the nicotinic acetylcholine receptors of the mouse diaphragm. The inhibitory action of MPTP on the contraction of the diaphragm is considered to play a role in the respiratory failure and muscle paralysis of intoxication with MPTP.