Examination of the role of central cholinergic mechanisms in the therapeutic effects of HI-6 in organophosphate poisoning.
In atropine-pretreated rats, HI-6 (125 mg/kg i.p.) raised the LD50 of Soman (subcutaneous) 5.7 times. Addition of HI-6 (25 micrograms i.c.v.) failed to enhance this protection further. HI-6 (intraperitoneal) also protected animals from intracerebroventricular Soman. HI-6, administered intracerebroventricularly either alone or in combination with intraperitoneal HI-6, failed to increase protection, nor did it reactivate Soman-inhibited acetylcholinesterase (AChE) in several brain areas. HI-6 (125 or 62.5 mg/kg i.p.) protected rats from Sarin lethality, but only the higher dose significantly altered the brain AChE activity. Furthermore, HI-6 (intraperitoneal) failed to block the Soman-induced increase in acetylcholine (ACh) or choline (Ch) levels in any of the brain areas examined. These data indicate that HI-6 is a very beneficial therapy against Soman, but that no definitive central anticholinergic activity of the compound could be found to explain its protective effects. It is possible that HI-6 acts by noncholinergic central mechanisms, or that it produces its beneficial effects outside the CNS. Furthermore, brain AChE activity does not appear to be indicative of protective effects of this oxime. ACh or Ch levels in this study were not good parameters to predict the outcome of Soman poisoning.
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D001285:Atropine / Q000494:pharmacology; D001921:Brain / Q000201:enzymology; D007276:Injections, Intraventricular; D007928:Lethal Dose 50; D008297:Male; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010091:Oximes; D011726:Pyridinium Compounds / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D012524:Sarin / Q000633:toxicity*; D012999:Soman / Q000008:administration & dosage / Q000633:toxicity*
D000931:Antidotes; D009943:Organophosphorus Compounds; D010091:Oximes; D011726:Pyridinium Compounds; D001285:Atropine; D012999:Soman; D012524:Sarin; D000110:Acetylcholinesterase; C022870:asoxime chloride