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ToxSci Advance Access published online on June 27, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg166
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received April 9, 2003; accepted June 3, 2003
© 2003 Society of Toxicology

Neurotoxicology

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

Lily Raveh 1*, Rachel Brandeis 1, Eran Gilat 1, Giora Cohen 1, David Alkalay 1, Ishai Rabinovitz 1, Hagar Sonego 1, and Ben Avi Weissman 1

1 Department of Pharmacology, Israel Institute for Biological Research, P.O. Box 19, Ness Ziona 74100, Israel

* To whom correspondence should be addressed. E-mail: lili{at}iibr.gov.il.


  Abstract

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 post exposure 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 five min after soman (1.2 LD50) whereas TAB (i.e., TMB4, atropine and benactyzine, 7.5, 3 and 1 mg/kg, respectively) was injected to rats concomitant with the development of toxic signs. Atropine (4 mg/kg) was given to the two former groups at 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 were noted ensuing caramiphen or TAB administration while scopolamine application resulted in a complex outcome: a part of the animals demonstrated no change in the number of these sites whereas the other 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, with the following rank order: 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 post exposure therapies against intoxication by organophosphates.

Key Words: TAB, caramiphen, scopolamine soman, Morris Water Maze EEG, peripheral benzodiazepine receptors .


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