Molecular Targets for Organophosphates in the Central Nervous System
Final rept. 18 May 1995-14 Mar 2006
MARYLAND UNIV BALTIMORE
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This project was a major effort to determine the effects of low-level exposure to the nerve agents sarin, soman, and VX in the mammalian CNS. Actions on synaptic transmission and neuronal cell death were assessed. Studies gave us clues to the mechanism of action of the agents, particularly in regard to cognitive function in humans that could be exposed to nerve agents in a chemical warfare attack. Reversible cholinesterase ChE inhibitors were tested for their ability to counteract nerve agent effects. Galantamine, a reversible ChE inhibitor with nicotinic allosteric potentiating actions currently used to treat mild to moderate Alzheimers disease, was found to be effective in counteracting nerve agent toxicity. In vitro studies were therefore employed to determine the mechanism of action of galantamine. In vivo studies in guinea pigs were ultimately begun to assess the effectiveness of a pre- andor post-treatment regimen of galantamine in protecting against multiple LD50 challenges with nerve agents. We compared the effectiveness of pre- and post-treatment with galantamine with other reversible ChE inhibitors in preventing lethality of the nerve agents and examined potential mechanisms underlying the effectiveness of the best treatment.
- Medicine and Medical Research