Anticholinergic and Antiglutamatergic Agents Protect against Soman-Induced Brain Damage and Cognitive Dysfunction

• Published in: Toxicological sciences 2003-09, Vol.75 (1), p.108-116
• Main Authors: Raveh, Lily, Brandeis, Rachel, Gilat, Eran, Cohen, Giora, Alkalay, David, Rabinovitz, Ishai, Sonego, Hagar, Weissman, Ben Avi
• Format: Article
• Language: English
• Subjects: Animals; Antidotes - pharmacology; Benzodiazepinones - metabolism; Biological and medical sciences; Brain - drug effects; Brain - metabolism; caramiphen; Chemical and industrial products toxicology. Toxic occupational diseases; chemoprotection; Cholinergic Antagonists - pharmacology; Cholinesterase Inhibitors - poisoning; Cognition Disorders - chemically induced; Cognition Disorders - physiopathology; Cognition Disorders - prevention & control; EEG; Electroencephalography; Excitatory Amino Acid Antagonists - pharmacology; Gas, fumes; In Vitro Techniques; Ligands; Male; Maze Learning - drug effects; Medical sciences; Morris water maze; peripheral benzodiazepine receptors; Radioligand Assay; Rats; Rats, Sprague-Dawley; scopolamine; soman; Soman - poisoning; TAB; Time Factors; Toxicology
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/kfg166

Soman, a powerful inhibitor of acetylcholinesterase, causes an array of toxic effects in the central nervous system including convulsions, learning and memory impairments, and, ultimately, death. We report on the protection afforded by postexposure antidotal treatments, combined with pyridostigmine (0.1 mg/kg) pretreatment, against these consequences associated with soman poisoning. Scopolamine (0.1 mg/kg) or caramiphen (10 mg/kg) were administered 5 min after soman (1.2 LD50), whereas TAB (i.e., TMB4, atropine, and benactyzine, 7.5, 3, and 1 mg/kg, respectively) was injected in rats concomitant with the development of toxic signs. Atropine (4 mg/kg) was given to the two former groups at the onset of toxic symptoms. Caramiphen and TAB completely abolished electrographic seizure activity while scopolamine treatment exhibited only partial protection. Additionally, no significant alteration in the density of peripheral benzodiazepine receptors was noted following caramiphen or TAB administration, while scopolamine application resulted in a complex outcome: a portion of the animals demonstrated no change in the number of these sites whereas the others exhibited markedly higher densities. Cognitive functions (i.e., learning and memory processes) evaluated using the Morris water maze improved considerably by the three treatments when compared to soman-injected animals; the following rank order was observed: caramiphen > TAB > scopolamine. Additionally, statistically significant correlations (r = 0.72, r = 0.73) were demonstrated between two learning parameters and [3H]Ro5-4864 binding to brain membrane. These results show that drugs with a pharmacological profile consisting of anticholinergic and antiglutamatergic properties such as caramiphen and TAB, have a substantial potential as postexposure therapies against intoxication by organophosphates.