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

作者：Wang Ying; Oguntayo Samuel; Wei Yanling; Wood Elisa; Brown Ammon; Jensen Neil; Auta James; Guiodotti Alessandro; Doctor Bhupendra P; Nambiar Madhusoodana P^*

来源：NeuroToxicology, 2012, 33(2): 169-177.

DOI：10.1016/j.neuro.2011.12.018

• Soman
• Imidazenil
• Neuroprotection
• Seizure
• Neuropathology
• Guinea pig

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 alpha 5-, alpha 2-, and alpha 3- but low intrinsic efficacy at alpha 1-containing GABA(A) 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 mu g/kg pyridostigmine bromide 30 min prior to 2 x 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 2x 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 GABA(A) 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. Published by Elsevier Inc.

• 出版日期2012-3