title: Neuroprotective effects of imidazenil against chemical warfare nerve agent soman toxicity in guinea pigs.
abstract: 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 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 μg/kg pyridostigmine bromide 30 min prior to 2× LD(50) soman exposure and 1 min later treated with a combination of 2mg/kg atropine sulfate and 25mg/kg 2-pralidoxime and various doses of imidazenil. Intramuscular administration of imidazenil, dose-dependently protected against 2× LD(50) of soman toxicity up to 1mg/kg. Further increase in the dose of imidazenil to 2.5mg/kg was less effective than 1mg/kg probably due to non-specific actions at sites other than GABA(A) receptors. Compared to vehicle group, 1mg/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.
authors.affiliation: Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Samuel
authors.initials: S
authors.lastname: Oguntayo
authors.forename: Yanling
authors.initials: Y
authors.lastname: Wei
authors.forename: Elisa
authors.initials: E
authors.lastname: Wood
authors.forename: Ammon
authors.initials: A
authors.lastname: Brown
authors.forename: Neil
authors.initials: N
authors.lastname: Jensen
authors.forename: James
authors.initials: J
authors.lastname: Auta
authors.forename: Alessandro
authors.initials: A
authors.lastname: Guiodotti
authors.forename: Bhupendra P
authors.initials: BP
authors.lastname: Doctor
authors.forename: Madhusoodana P
authors.initials: MP
authors.lastname: Nambiar
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001285:Atropine / Q000627:therapeutic use; D001569:Benzodiazepines / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000627:therapeutic use; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004562:Electrocardiography / Q000379:methods; D004569:Electroencephalography / Q000379:methods; D006168:Guinea Pigs; D007093:Imidazoles / Q000627:therapeutic use*; D007928:Lethal Dose 50; D008297:Male; D018727:Muscarinic Antagonists / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000209:etiology*; D011220:Pralidoxime Compounds / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D012999:Soman / Q000633:toxicity*; D013686:Telemetry; D013997:Time Factors
chemical_list: D002619:Chemical Warfare Agents; D002801:Cholinesterase Reactivators; D007093:Imidazoles; D018727:Muscarinic Antagonists; D018696:Neuroprotective Agents; D011220:Pralidoxime Compounds; D001569:Benzodiazepines; D001285:Atropine; C082661:imidazenil; D012999:Soman; D000110:Acetylcholinesterase; C028797:pralidoxime