The Anticholinergic and Antiglutamatergic Drug Caramiphen Reduces Seizure Duration in Soman-Exposed Rats: Synergism with the Benzodiazepine Diazepam
ARMY MEDICAL RESEARCH INST OF CHEMICAL DEFENSE ABERDEEN PROVING GROUND MD
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Therapy of seizure activity following exposure to the nerve agent soman GD includes treatment with the anticonvulsant diazepam DZP, an allosteric modulator of -aminobutyric acid A GABAA receptors. However, seizure activity itself causes the endocytosis of GABAA receptors and diminishes the inhibitory effects of GABA, thereby reducing the efficacy of DZP. Treatment with an N-methyl-D-aspartic acid NMDA receptor antagonist prevents this reduction in GABAergic inhibition.We examined the efficacy of the NMDA receptor antagonist caramiphen edisylate CED 20mgkg, im and DZP 10 mgkg, sc, administered both separately and in combination, at 10, 20 or 30 min following seizure onset for attenuation of the deleterious effects associated with GD exposure 1.2 LD50 132 gkg, sc in rats. Outcomes evaluated were seizure duration, neuropathology, acetylcholinesterase AChE activity, body weight, and temperature. We also examined the use of the reversible AChE inhibitor physostigmine PHY 0.2 mgkg, im as a therapy for GD exposure.We found that the combination of CED and DZP yielded a synergistic effect, shortening seizure durations and reducing neuropathology compared to DZP alone, when treatment was delayed 20 30 min after seizure onset. PHY reduced the number of animals that developed seizures, protected a fraction of AChE from GD inhibition, and attenuated postexposure body weight and temperature loss independent of CED andor DZP treatment. We conclude that 1 CED and DZP treatment offers considerable protection against the effects of GD and 2 PHY is a potential therapeutic option following GD exposure, albeit with a limited window of opportunity.
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