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Multiple Actions of Anticholinesterase Agents on Chemosensitive Synapses: Molecular Basis for Prophylaxis and Treatment of Organophosphate Poisoning

1985; Oxford University Press; Volume: 5; Issue: 6part2 Linguagem: Inglês

10.1093/toxsci/5.6part2.182

1096-6080

Edson X. Albuquerque, S.S. Deshpande, M. KAWABUCHI, Y. ARACAVA, Mohamed Omar Mahmoud Idriss, D. L. RICKETT, A. F. BOYNE,

Cholinesterase and Neurodegenerative Diseases

Multiple Actions of Anticholinesterase Agents on Chemosensitive Synapses: Molecular Basis for Prophylaxis and Treatment of Organophosphate Poisoning. ALBUQUERQUE, E. X., DESHPANDE, S. S., KAWABUCHI, M., ARACAVA, Y., IDRISS, M., RICKETT, D. L, AND BOYNE, A. F. (1985). Fundam. Appl. Toxicol. 5, S182–S2O3. The present study demonstrates that the reversible and irreversible anti-ChE agents have direct actions on the nicotinic acetylcholine receptor-ionic channel (AChR) and on the locust glutamatergic neuromuscular junction. In addition, the prophylaxis of lethality of organophosphorus anti-ChE compounds was studied. The lethality of VX and sarin was diminished when the rats were pretreated with physostigmine and atropine. The effectiveness of this protection, however, was markedly increased when a ganglionic blocker, either mecamylamine or chlorisondamine, was added, such that all the animals survived after receiving four times a lethal dose of VX. Pretreated animals receiving sarin showed significant recovery of morphological and functional properties of the neuromuscular junction as compared to the damage of structures from animals without pretreatment. Blood ChE inhibition was slightly decreased while brain and muscle AChE levels were significantly recovered (from 98 and 70% to 56 and 32%, respectively) by the pretreatment. This effect may partially explain the protection given by physostigmine but not that afforded by addition of a non-anti-ChE agent. Physostigmine, at concentrations >20 μM, showed both a marked depression of the peak amplitudes of the end-plate current (EPC) and a shortening of the decay time constants TEPC. These effects were mostly due to a direct drug interaction with the nicotinic AChR blocking the ionic channel in its open conformation. Single-channel recordings showed that physostigmine decreases conductance and open times of the channels activated in the presence of ACh and in addition has an agonistic property on the nicotinic AChR. VX, on the other hand, only shortened the open times of ACh-activated channels without affecting the conductance. No agonist property was detected with VX. On glutamatergic synapses, the ChE inhibitors generated spontaneous firing of end-plate potentials (EPPs) and action potentials (APs). This effect was blocked in the presence of low external Ca2+ concentration or tetrodotoxin. It seems that the spontaneous EPP and AP firing resulted from an increased transmitter release induced by an increase in Na+ influx at the presynpatic nerve terminal. Physostigmine and some irreversible ChE inhibitors (VX and DFP) also blocked the postjunctional glutamate receptors. Similar to the nicotinic AChR, this effect was mostly related to a blockade of the open channels. In conclusion, the present studies showed significant protection of rats by physostigmine in combination with some ganglionic antagonists against lethality by organophosphate agents. They also revealed direct action of reversible and irreversible ChE inhibitors on the nicotinic and glutamatergic synapses which could account for some of the observed effects.