The anticholinergic and antiglutamatergic drug caramiphen reduces seizure duration in soman-exposed rats: Synergism with the benzodiazepine diazepam

• Published in: Toxicology and applied pharmacology Vol. 259; no. 3; pp. 376 - 386
• Main Authors: Schultz, M.K., Wright, L.K.M., Stone, M.F., Schwartz, J.E., Kelley, N.R., Moffett, M.C., Lee, R.B., Lumley, L.A.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15.03.2012; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Acetylcholinesterase - metabolism; AMINOBUTYRIC ACID; Animals; Anticonvulsants - administration & dosage; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; ASPARTIC ACID; Biological and medical sciences; Body Temperature - drug effects; Body Weight - drug effects; Caramiphen; Chemical and industrial products toxicology. Toxic occupational diseases; Cholinergic Antagonists - administration & dosage; Cholinergic Antagonists - pharmacology; Cholinesterase Inhibitors - toxicity; Cyclopentanes - administration & dosage; Cyclopentanes - pharmacology; Diazepam; Diazepam - administration & dosage; Diazepam - pharmacology; Dose-Response Relationship, Drug; Drug Synergism; ESERINE; Gas, fumes; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; INHIBITION; Male; Medical sciences; Nervous system (semeiology, syndromes); Neurology; Neuropharmacology; Neuroprotection; Pharmacology. Drug treatments; Physostigmine; RATS; Rats, Sprague-Dawley; RECEPTORS; Seizure; Seizures - chemically induced; Seizures - drug therapy; Soman; Soman - toxicity; SYNERGISM; THERAPY; Time Factors; Toxicology; WEIGHT; Neuroprotection; Physostigmine; Seizure; Soman; Diazepam; Caramiphen; Antiglaucomatous agent; Rat; Psychotropic; Epilepsy; Esterases; Anticonvulsant; Synergism; Chemical warfare agent; Alkaloid; Cholinergic receptor; Benzodiazepine derivatives; Drug interaction; Antagonist; Anticholinesterase agent; Neurological disorder; Drug; Nervous system diseases; Toxic gas; Enzyme; Rodentia; Enzyme inhibitor; Hypnotic; Antiparkinson agent; Cholinesterase; Carboxylic ester hydrolases; Cerebral disorder; Vertebrata; Anticholinergic agent; Mammalia; Tranquillizer; Convulsion; Animal; Central nervous system disease; Hydrolases; Organophosphorus compounds; Muscarinic receptor
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2012.01.017

Therapy of seizure activity following exposure to the nerve agent soman (GD) includes treatment with the anticonvulsant diazepam (DZP), an allosteric modulator of γ-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; 20mg/kg, im) and DZP (10mg/kg, sc), administered both separately and in combination, at 10, 20 or 30min following seizure onset for attenuation of the deleterious effects associated with GD exposure (1.2 LD50; 132μg/kg, 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; 0.2mg/kg, 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 20–30min after seizure onset. PHY reduced the number of animals that developed seizures, protected a fraction of AChE from GD inhibition, and attenuated post-exposure body weight and temperature loss independent of CED and/or 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. ► Soman (GD) produced seizure activity resulting in neuropathology in rats. ► Tx: caramiphen (CED) and/or diazepam (DZP) @ 10, 20 or 30 min after seizure onset. ► CED/DZP showed superior anticonvulsant and neuroprotective capacity. ► Physostigmine (PHY) was examined as an adjunct post-exposure therapy. ► PHY attenuated GD-induced seizure development, but not seizure duration.