Pre-junctional effects of oximes on [3H]-acetylcholine release in rat hippocampal slices during soman intoxication.
In this study, the non-reactivating effects of oximes in the hippocampus of the rat are investigated. The potassium (51 mM) evoked release of [(3)H]-acetylcholine and the liberation of [(3)H]-choline were determined in hippocampal slices following in vitro exposure to soman and five oximes (toxogonin, HI-6, HLö-7, P2S and 2-PAM) in separate experiments by superfusion. In the absence of soman, toxogonin and HLö-7 in particular induced a concentration dependent significant increase in the evoked release of [(3)H]-acetylcholine. There was also a significant effect of HI-6, but the effect was much smaller. Two pralidoxime salts, P2S (methanesulfonate salt) and 2-PAM (methiodide salt), had similar but lower effects that were only observed at relatively high concentrations. Experiments performed following complete inhibition of the acetylcholinesterase activity by soman (1.0 microM) showed that HI-6 and HLö-7 induced a significant decrease in the potassium-evoked release of [(3)H]-acetylcholine, while the liberation of [(3)H]-choline increased. Toxogonin, P2S and 2-PAM did not reduce significantly the evoked release of [(3)H]-acetylcholine. Only limited reactivation of the acetylcholinesterase activity was observed in superfusion experiments with toxogonin, HI-6, P2S and 2-PAM following exposure of hippocampal slices to soman. However, HLö-7 was proved to be relatively more effective in reactivating the acetylcholinesterase activity at high concentrations (50 and 200 microM). The acetylcholinesterase activity was reactivated to approximately 12% and 40% of control, respectively. It is concluded that HI-6 and HLö-7 have important non-acetylcholinesterase reactivating properties following soman poisoning, as may be seen by the significant reduction in the evoked release of [(3)H]-acetylcholine effected by these oximes. HLö-7 is of particular interest in view of its ability to additionally improve reactivation of the acetylcholinesterase activity.
Øydvin
Ole Kristian
OK
Norwegian Defence Research Establishment, Protection Division, Postbox 25, NO-2027 Kjeller, Norway.
Tansø
Rita
R
Aas
Pål
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D000109:Acetylcholine / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009469:Neuromuscular Junction / Q000187:drug effects; D009768:Obidoxime Chloride / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012999:Soman / Q000633:toxicity*; D014316:Tritium
D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D011220:Pralidoxime Compounds; D011725:Pyridines; D011726:Pyridinium Compounds; D014316:Tritium; C058577:HLo 7; D009768:Obidoxime Chloride; D012999:Soman; D000110:Acetylcholinesterase; C022870:asoxime chloride; D000109:Acetylcholine; C028797:pralidoxime; D011188:Potassium