Therapeutic Effects of Drug Combinations Targeting Muscarinic and Adrenoreceptors during Soman Poisoning

Abstract

Soman, a potent acetylcholinesterase inhibitor, induces accumulation of acetylcholine at the neural synapses resulting in overstimulation of the cholinergic system. At lethal concentrations, Soman-induced seizures progress rapidly into status epilepticus, which if not terminated, will lead to eventual death or profound brain damage amongst survivors. The current diazepam anticonvulsant could stop seizures when administrated early but its efficacy diminishes rapidly when applied late post seizures. Increasing diazepam dosage to compensate for reduction in anticonvulsant potency enhances nerve agent-induced respiratory depression. Research is on-going to identify alternate neuroprotection options for managing established and refractory status epilepticus without increasing respiratory difficulties amongst nerve agent casualties. In this chapter, a review of the various neuroprotection options that have been investigated as alternatives to diazepam in the last decade is presented. In addition, we have also provided a comprehensive report on neuroprotective actions achieved with a combined administration of clonidine and atropine sulfate in Soman poisoned animals with status epilepticus. Clonidine, an α2-adrenergic agonist, acts on post-synaptic heteroreceptors to exert pre-synaptic inhibition on release of acetylcholine while atropine sulphate, as a muscarinic antagonist, blocks cholinergic activation of post-synaptic muscarinic receptors. By targeting the central cholinergic system with this synergistic drug combination, besides enhancing animal survival, rapid seizure arrest was achieved with early administration while functional neuroprotection was observed in animals undergoing established status epilepticus. Interestingly, neuroprotection was achieved despite the continued presence of seizures, when it was applied during established status epilepticus and its effect was much higher than that afforded by diazepam. Inclusion of clonidine was vital for preventing atropine induced lethal ventricular arrhythmias in hypoxic animals when treatment was given late. This finding may be useful for reviewing the current perceived roles of central cholinergic and glutamatergic systems in maintaining established status epilepticus, which has directed much of current research for new neuroprotection options towards the glutamate system.