Imidazenil: a potent and safe protective agent against diisopropyl fluorophosphate toxicity

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 imidazemil (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. (C) 2003 Elsevier Ltd. All rights reserved.