Protection against Acetylcholinesterase Inhibitor Toxicity by Alpha-Adrenergic Agonists: A Toxicological and Neurochemical Study

摘要

Soman produced a dose-dependent increase in lethality over a narrow concentration range. Soman produced time- and dose-dependent increases in tremor, salivation, hind limb extention, convulsions, and chewing behaviors, as well as decreases in three normal stereotyped behaviors, sniffing, locomotion and rearing. Atropine and clonidine were equally effective at limiting soman-induced lethality and behavioral changes. The protective effects of clonidine and atropine were additive or synergistic, even though clonidine antagonizes some of the stereotyped behaviors elicited by atropine. A wide degree of interaction with cholinesterase was observed among the adrenergic agonists examined. However, the more potent drugs (with respect to protective activity in the mouse) such as clonidine, the ICI compounds, lofexidine and guanabenz exhibited the lowest Ki's for the enzyme. Alternatively, the lower potency compounds such as azepexole, ST 95 and guanfacine exhibited much higher Ki values. This relationship suggests the importance of this interaction with cholinesterase for their protective ability. The protective potencies of adrenergic agonists obtained from our earlier mouse study were also correlated well with their abilities to interact with 3H clonidine binding sites in vitro. Thus, clonidine not only offers protection against soman lethality and behavioral toxicity through several potential mechanisms, it also reduces atropine-induced side effects when the two agents are employed together. Keywords: Acetylcholinesterase inhibitor toxicity, Soman, Protective regimen, Clonidine, Atropine, Behavior, Cholinesterase, Muscarinic receptors, Adrenergic receptors.