Caramiphen edisylate as adjunct to standard therapy attenuates soman-induced seizures and cognitive deficits in rats

• Published in: Neurotoxicology and teratology Vol. 44; pp. 89 - 104
• Main Authors: Schultz, M.K, Wright, L.K.M, de Araujo Furtado, M, Stone, M.F, Moffett, M.C, Kelley, N.R, Bourne, A.R, Lumeh, W.Z, Schultz, C.R, Schwartz, J.E, Lumley, L.A
• Format: Journal Article
• Language: English
• Published: United States 01-07-2014
• Subjects: Animals; Anticonvulsants - therapeutic use; Atropine - therapeutic use; Body Temperature - drug effects; Body Weight - drug effects; Brain - drug effects; Brain - pathology; Cholinesterase Inhibitors - toxicity; Cognition Disorders - chemically induced; Cognition Disorders - drug therapy; Cyclopentanes - therapeutic use; Diazepam - therapeutic use; Drug Therapy, Combination; Emergency; Locomotion - drug effects; Male; Maze Learning - drug effects; Medical Education; Oximes - therapeutic use; Pyridinium Compounds - therapeutic use; Rats; Rats, Sprague-Dawley; Seizures - chemically induced; Seizures - drug therapy; Soman - toxicity; Rats; Anticonvulsant; Chemical warfare nerve agents; Soman; Behavior; Caramiphen
• ISSN: 0892-0362; 1872-9738
• DOI: 10.1016/j.ntt.2014.06.002

Abstract The progression of epileptiform activity following soman (GD) exposure is characterized by a period of excessive cholinergic activity followed by excessive glutamatergic activity resulting in status epilepticus , which may lead to neuropathological damage and behavioral deficits. Caramiphen edisylate is an anticholinergic drug with antiglutamatergic properties, which conceptually may be a beneficial therapeutic approach to the treatment of nerve agent exposure. In the present study, rats were exposed to 1.2 LD50 GD or saline, treated with atropine sulfate (2 mg/kg, im) and HI-6 (93.6 mg/kg, im) 1 min after GD exposure, and monitored for seizure activity. Rats were treated with diazepam (10 mg/kg, sc) and caramiphen (0, 20 or 100 mg/kg, im) 30 min after seizure onset. Following GD exposure, performance was evaluated using a battery of behavioral tests to assess motor coordination and function, sensorimotor gating, and cognitive function. Caramiphen as adjunct to diazepam treatment attenuated GD-induced seizure activity, neuropathological damage, and cognitive deficits compared to diazepam alone, but did not attenuate the GD-induced sensorimotor gating impairment. These findings show that physiological, behavioral, and neuropathological effects of GD exposure can be attenuated by treatment with caramiphen as an adjunct to therapy, even if administration is delayed to 30 min after seizure onset.