Neuroprotective effects of imidazenil against chemical warfare nerve agent soman toxicity in guinea pigs

The chemical warfare nerve agent, soman irreversibly inhibits acetylcholinesterase (AChE) leading to hypercholinergy and seizures which trigger glutamate toxicity and status epilepticus ultimately resulting in neuropathology and neurobehavioral deficits. The standard emergency treatment comprising of anticholinergic, AChE reactivator and anticonvulsant does not completely protect against soman toxicity. We have evaluated imidazenil, a new anticonvulsant imidazo benzodiazepine with high affinity and intrinsic efficacy at α5-, α2-, and α3- but low intrinsic efficacy at α1-containing GABAA receptors and is devoid of cardiorespiratory depression, sedative/hypnoitc and amnestic actions and does not elicit tolerance and dependence liabilities unlike diazepam, for protection against soman toxicity. Guinea pigs implanted with bipotential radiotelemetry probes for recording EEG and ECG were administered with 26 μg/kg pyridostigmine bromide 30 min prior to 2× LD50 soman exposure and 1 min later treated with a combination of 2 mg/kg atropine sulfate and 25 mg/kg 2-pralidoxime and various doses of imidazenil. Intramuscular administration of imidazenil, dose-dependently protected against 2× LD50 of soman toxicity up to 1 mg/kg. Further increase in the dose of imidazenil to 2.5 mg/kg was less effective than 1 mg/kg probably due to non-specific actions at sites other than GABAA receptors. Compared to vehicle group, 1 mg/kg imidazenil treatment showed optimal increase in survival rate, reduction in behavioral manifestations and high power of EEG spectrum as well as neuronal necrosis. These data suggest that imidazenil is an effective anticonvulsant for medical countermeasure against soman-induced toxicity.

► Evaluation of a new anticonvulsant imidazenil for protection against nerve agents.
► Critically important anticonvulsant with no cardio-respiratory depression for protection.
► Demonstration of dose-dependent efficacy by mortality, behavior, EEG and pathology.
► Development of an ideal drug to replace the currently approved anticonvulsants.