Spin trapping agent phenyl-N-tert-butylnitrone prevents diisopropylphosphorofluoridate-induced excitotoxicity in skeletal muscle of the rat.
Indirect evidence suggests that reactive oxygen species (ROS) may mediate muscle fiber necrosis following muscle hyperactivity induced by the anticholinesterase diisopropylphosphorofluoridate (DFP). Pronounced muscle fasciculations and muscle fiber necrosis were seen when acetylcholinesterase (AChE) activity was reduced to less than 30% of control. The spin trapping agent phenyl-N-tert-butylnitrone (PBN) was used in vivo to directly assess the formation of ROS during DFP (1.75 mg/kg, s.c.) induced muscle hyperactivity. Pretreatment with PBN (300 mg/kg, i.p.), the concentration necessary for in vivo spin trapping, prevented muscle hyperactivity as well as necrosis and attenuated the DFP induced AChE inhibition otherwise seen in DFP only treated rats. PBN had no effect when given after fasciculations were established. Muscle extracts from PBN and DFP treated rats subjected to electron spin resonance (ESR) spectroscopy tested negative for ROS. While the role of PBN as an antioxidant is well established, its prophylactic effect against excitotoxity induced by an AChE inhibitor are due to its protection of AChE, an unexpected non-antioxidant action.
Milatovic
D
D
Department of Pharmacology and Neurology, Vanderbilt University, School of Medicine, Nashville, TN 37212, USA.
Zivin
M
M
Hustedt
E
E
Dettbarn
W D
WD
D000110:Acetylcholinesterase / Q000502:physiology*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D003497:Cyclic N-Oxides; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005207:Fasciculation / Q000139:chemically induced / Q000517:prevention & control*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007531:Isoflurophate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology; D009336:Necrosis; D009589:Nitrogen Oxides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D013113:Spin Labels
D002800:Cholinesterase Inhibitors; D003497:Cyclic N-Oxides; D018690:Excitatory Amino Acid Agonists; D016166:Free Radical Scavengers; D018727:Muscarinic Antagonists; D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; D007531:Isoflurophate; C029217:phenyl-N-tert-butylnitrone; D001285:Atropine; D000110:Acetylcholinesterase