Protection against soman-induced seizures in rats: relationship among doses of prophylactics, soman, and adjuncts.
The combined effects of physostigmine and procyclidine (antagonizing muscarinic, nicotinic, and NMDA receptors) were tested against various doses of soman. Physostigmine (0.1 mg/kg) in combination with procyclidine doses of 1, 3, or 6 mg/kg effectively prevented the development of convulsions and hippocampally monitored seizures when the doses of soman were 1.3, 1.6, or 2 x LD50, respectively. Results from [(3)H]MK-801-binding experiments showed that procyclidine inhibits the phencyclidine site at the NMDA receptor in a concentration-dependent manner. Physostigmine (0.1 mg/kg) and procyclidine in a dose of 1 mg/kg did not prevent convulsions or seizures when the soman dose was 1.6 x LD50. Subsequent treatment with scopolamine in doses of 0.5 or 1 mg/kg immediately after (3 min) seizure onset showed that only the highest dose produced a reliable termination. When scopolamine (1 mg/kg) was given later (10 min) after onset of seizures, no effect was obtained. The sustained seizures were subsequently treated with diazepam (10 mg/kg) and pentobarbital (30 mg/kg) and finally terminated 25 min after onset. In rats given inadequate prophylaxis, both modified convulsions and seizures were seen. It is suggested that moderate doses of prophylactics should be preferred to avoid adverse effects on cognitive functions because insufficient prophylaxis can be compensated for by adjunct treatment.
Myhrer
Trond
T
Division for Protection and Materiel, Norwegian Defence Research Establishment, PO Box 25, NO-2027 Kjeller, Norway. trond.myhrer@ffi.no
Nguyen
Nga H T
NH
Andersen
Jannike M
JM
Aas
Pål
P
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D003292:Convulsants / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D016291:Dizocilpine Maleate / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018727:Muscarinic Antagonists / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000378:metabolism; D010830:Physostigmine / Q000627:therapeutic use; D011352:Procyclidine / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control; D012999:Soman / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*
D002800:Cholinesterase Inhibitors; D003292:Convulsants; D018727:Muscarinic Antagonists; D018696:Neuroprotective Agents; D016291:Dizocilpine Maleate; D012999:Soman; D010830:Physostigmine; D011352:Procyclidine; D012601:Scopolamine