Pharmacological Screening of Anticonvulsants against Nerve Agents: Limitations by Conventional Approach

Nerve agents are highly toxic organophosphate compounds that irreversibly inhibit acetylcholinesterase, the enzyme hydrolysing acetylcholine. Accumulation of acetylcholine results in respiratory dysfunction, prolonged seizures, convulsive status epilepticus, and death. The progression of events can be divided into three phases. An early phase lasting from exposure to about 5 minutes after seizure onset is dominated by excessive cholinergic activity followed by a transitional phase of cholinergic and glutamatergic hyperactivity, and finally a predominantly glutamatergic phase after about 40 minutes. Nerve agent induced seizures that have lasted more than 10 min appears to be difficult to terminate, unless the countermeasures exert cholinergic and glutamatergic antagonism as well as GABAergic agonism. However, even medical therapies assuring such effects become gradually less effective by elapse of time (1 h). It will take at least 30 min for emergency personnel to access individuals unprepared for exposure to nerve agent. Even soldiers properly equipped with a protective mask, gloves, and clothes may need medical help, because bad training, bad discipline or bad luck can lead to intoxication by nerve agent. Hence, there is an urgent need for strategies capable of terminating nerve agent-induced seizures well after their onset. A triple regimen consisting of procyclidine (6 mg/kg), diazepam (10 mg/kg)