Diisopropylphosphorofluoridate-induced cholinergic hyperactivity and lipid peroxidation.
In the present study, the association between acetylcholine (ACh)-induced muscle necrosis and the appearance of lipid peroxidation products was investigated. Lipid peroxidation in this injury was quantified by the malondialdehyde-thiobarbituric acid complex (TBA-MDA) using HPLC. To induce muscle necrosis, rats were treated with 1.0 or 2.0 mg/kg diisopropylphosphorofluoridate (DFP), an irreversible inhibitor of AChE that induced muscle fasciculations, and were euthanized 30-120 min after the DFP treatment. DFP caused a dose-dependent increase in AChE inhibition, muscle fasciculations, TBA-MDA formation, and muscle necrosis. Reduction of glutathione (GSH) by pretreatment with buthionine sulfoximine (BSO) potentiated the DFP-induced changes in TBA-MDA and caused an increase in the number of necrotic muscle fibers. Prevention of fasciculations by pretreatment with cholinergic antagonists such as atropine and d-tubocurarine, before DFP, inhibited the increase in lipid peroxidation, and significantly attenuated the muscle fiber necrosis. Without affecting muscle fasciculations, the antioxidant U-78517F prevented the increase in lipid peroxidation and reduced the number of muscle fibers that became necrotic. It is suggested that DFP-induced AChE inhibition causes pronounced muscle hyperactivity as the initial step that triggers free radical-induced lipid peroxidation as the final common pathway to muscle injury.
Yang
Z P
ZP
Department of Pharmacology, Vanderbilt University Medical School, Nashville, Tennessee 37212, USA.
Dettbarn
W D
WD
D015104:3,4-Methylenedioxyamphetamine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D019328:Buthionine Sulfoximine; D002799:Cholinergic Fibers / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002839:Chromans / Q000494:pharmacology; D003964:Diaphragm / Q000201:enzymology / Q000473:pathology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals; D005978:Glutathione / Q000378:metabolism; D007531:Isoflurophate / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000139:chemically induced; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013858:Thiobarbiturates / Q000378:metabolism; D014403:Tubocurarine / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D002839:Chromans; D016166:Free Radical Scavengers; D005609:Free Radicals; D010879:Piperazines; D013858:Thiobarbiturates; D007531:Isoflurophate; C066382:U 78517F; D008717:Methionine Sulfoximine; D015104:3,4-Methylenedioxyamphetamine; D019328:Buthionine Sulfoximine; D000110:Acetylcholinesterase; D005978:Glutathione; C029684:thiobarbituric acid; D014403:Tubocurarine