Tertiary Oximes on Brain Acetylcholinesterase and Central Excitatory Effects of Nerve Agents
ARMY MEDICAL RESEARCH INST OF CHEMICAL DEFENSE ABERDEEN PROVING GROUND MD
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Abstract. Organophosphorus nerve agents irreversibly inhibit the enzyme acetylcholinesterase AChE, which leads to an excess of the cholinergic neurotransmitter acetylcholine in the synapses causing numerous toxic effects, including prolonged seizures and subsequent neuropathology. Current nerve agent therapies include pralidoxime 2-PAM to reactivate inhibited AChE. The quaternary structure of this oxime does not allow it to cross the blood brain barrier BBB to reactivate brain AChE and to mitigate CNS toxicity. This study examined whether monoisonitrosoacetone MINA and N,N-diethyl-3-2-hydroxyiminoacetoxy propan-1-aminium chloride DHAP, two tertiary oximes that can penetrate the BBB, could prevent or reverse the central toxic effects of three nerve agents, sarin GB, cyclosarin GF, or VX, in guinea pigs. The first experiment tested whether MINA and DHAP could reactivate brain and peripheral tissue AChE inhibited by these nerve agents. Animals were challenged with a 1.0 x LD50 subcutaneous dose of a nerve agent and followed 15 min by one of 5 test doses of the oxime.
- Chemical, Biological and Radiological Warfare