Convulsions are major and life-threatening signs of
organophosphate (OP)
nerve agents induced neurotoxicity. Thus, early intervention with
anticonvulsant drugs to control seizure propagation and the consequent irreversible neuronal damage that may occur during OP exposure is essential.
Diazepam is the standard
anticonvulsant used in the therapeutic management of OP
poisoning. However, its use has been associated with several unwanted effects including, sedation,
amnesia, and in the large doses used for such treatment,
respiratory depression. Moreover, protracted administration of
diazepam has been associated with tolerance and dependence liabilities. In this study, we compared the efficacy and safety of
diazepam (full allosteric modulator of
GABA action) to that of
imidazenil (partial, selective allosteric modulator of
GABA action) as preventive treatment against diisopropyl
fluorophosphate (
DFP)-induced convulsions and mortality. Our results show that
imidazenil is more potent and efficacious than
diazepam in protecting rats against
DFP-induced convulsions and death. Moreover,
imidazenil was effective at doses (1 and 0.5 mg/kg) we have previously shown to be devoid of sedation,
amnesia,
respiratory depression, or tolerance and/or dependence. In contrast,
diazepam was effective at doses (5 and 2.5 mg/kg) that produce sedation,
amnesia, and
ataxia. Furthermore, the combination of
imidazenil with
atropine was more potent and efficacious than that with
diazepam.