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

• DOI: 10.1016/j.ntt.2014.06.002
• Publication Date: 2014-06-16T16:42:33Z
• Authors: M.K. Schultz; L.K.M. Wright; M. de Araujo Furtado; M.F. Stone; M.C. Moffett; N.R. Kelley; A.R. Bourne; W.Z. Lumeh; C.R. Schultz; J.E. Schwartz; L.A. Lumley
• Keywords: Atropine; Male; 0301 basic medicine; Diazepam; Body Weight; Soman; Brain; Pyridinium Compounds; Cyclopentanes; Body Temperature; Rats; 3. Good health; Rats, Sprague-Dawley; 03 medical and health sciences; 0302 clinical medicine; Seizures; Oximes; Animals; Anticonvulsants; Drug Therapy, Combination; Cholinesterase Inhibitors; Cognition Disorders; Maze Learning; Locomotion

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 (2mg/kg, im) and HI-6 (93.6mg/kg, im) 1min after GD exposure, and monitored for seizure activity. Rats were treated with diazepam (10mg/kg, sc) and caramiphen (0, 20 or 100mg/kg, im) 30min 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 30min after seizure onset.