Organophosphate-induced convulsions and prevention of neuropathological damages.
Such organophosphorus (OP) compounds as diisopropylfluorophosphate (DFP), sarin and soman are potent inhibitors of acetylcholinesterases (AChEs) and butyrylcholinesterases (BChEs). The acute toxicity of OPs is the result of their irreversible binding with AChEs in the central nervous system (CNS), which elevates acetylcholine (ACh) levels. The protective action of subcutaneously (SC) administered antidotes or their combinations in DFP (2.0 mg/kg BW) intoxication was studied in 9-10-weeks-old Han-Wistar male rats. The rats received AChE reactivator pralidoxime-2-chloride (2PAM) (30.0 mg/kg BW), anticonvulsant diazepam (2.0 mg/kg BW), A(1)-adenosine receptor agonist N(6)-cyclopentyl adenosine (CPA) (2.0 mg/kg BW), NMDA-receptor antagonist dizocilpine maleate (+-MK801 hydrogen maleate) (2.0 mg/kg BW) or their combinations with cholinolytic drug atropine sulfate (50.0 mg/kg BW) immediately or 30 min after the single SC injection of DFP. The control rats received atropine sulfate, but also saline and olive oil instead of other antidotes and DFP, respectively. All rats were terminated either 24 h or 3 weeks after the DFP injection. The rats treated with DFP-atropine showed severe typical OP-induced toxicity signs. When CPA, diazepam or 2PAM was given immediately after DFP-atropine, these treatments prevented, delayed or shortened the occurrence of serious signs of poisoning. Atropine-MK801 did not offer any additional protection against DFP toxicity. In conclusion, CPA, diazepam and 2PAM in combination with atropine prevented the occurrence of serious signs of poisoning and thus reduced the toxicity of DFP in rat.
Tuovinen
Kai
K
Department of Physiology, University of Kuopio, P.O. Box 1627, SF-70211 Kuopio, Finland.
D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D001285:Atropine / Q000037:antagonists & inhibitors / Q000633:toxicity; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D003975:Diazepam / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D007531:Isoflurophate / Q000037:antagonists & inhibitors / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D011220:Pralidoxime Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced*
D000931:Antidotes; D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018757:GABA Modulators; D009419:Nerve Tissue Proteins; D009943:Organophosphorus Compounds; D011220:Pralidoxime Compounds; D007531:Isoflurophate; C048599:N(6)-cyclopentyladenosine; D016291:Dizocilpine Maleate; D001285:Atropine; D000110:Acetylcholinesterase; D000241:Adenosine; D003975:Diazepam