Potential of memantine, D-tubocurarine, and atropine in preventing acute toxic myopathy induced by organophosphate nerve agents: soman, sarin, tabun and VX.
Male Sprague-Dawley rats when administered sc a sublethal dose of organophosphorus cholinesterase inhibitors such as the nerve agents, soman (100 micrograms/kg, sc), sarin (110 micrograms/kg, sc), tabun (200 micrograms/kg, sc), or VX (12 micrograms/kg, sc), developed seizures and severe muscle fasciculations within 15-20 min, lasting for 4-6 hr. Marked inhibition of acetylcholinesterase (AChE) and necrotic lesions in skeletal muscles such as soleus, extensor digitorum longus, and diaphragm were evident between 1-24 hr following injection. Pretreatment with memantine HCl (MEM, 18 mg/kg, sc) together with atropine sulfate (ATS, 16 mg/kg, sc), 60 min and 15 min, respectively, prior to nerve agents attenuated AChE inhibition, prevented myonecrosis, and muscle fasciculations as well as other signs of cholinergic toxicity. Pretreatment combining d-tubocurarine (d-TC, 0.075 mg/kg, sc) and ATS (16 mg/kg, sc) prevented the myonecrosis and fasciculation without protecting AChE against inhibition by these nerve agents. Neither MEM, d-TC, nor ATS in the concentration given interfered with the normal behavior of the rats. The role of d-TC and ATS interaction with presynaptic receptors regulating ACh release and MEM's role in modulating neural hyperactivity as protective mechanisms are discussed.
Gupta
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RC
Toxicology Department, Murray State University, Hopkinsville, Kentucky 42241.
Dettbarn
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WD
D000110:Acetylcholinesterase / Q000378:metabolism; D000208:Acute Disease; D000818:Animals; D001285:Atropine / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D009135:Muscular Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D010755:Organophosphates / Q000037:antagonists & inhibitors; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors*; D009946:Organothiophosphorus Compounds / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012524:Sarin / Q000037:antagonists & inhibitors; D012999:Soman / Q000037:antagonists & inhibitors; D014403:Tubocurarine / Q000494:pharmacology*
D000110:Acetylcholinesterase; D001285:Atropine; D002800:Cholinesterase Inhibitors; D008559:Memantine; D010755:Organophosphates; D009943:Organophosphorus Compounds; D009946:Organothiophosphorus Compounds; D012524:Sarin; D012999:Soman; D014403:Tubocurarine; C009680:VX-agent; C009374:tabun