The combination of donepezil and procyclidine protects against soman-induced seizures in rats.
Current treatment of nerve agent poisoning consists of prophylactic administration of pyridostigmine and therapy using atropine, an oxime and a benzodiazepine. Pyridostigmine does however not readily penetrate the blood-brain barrier giving ineffective protection of the brain against centrally mediated seizure activity. In this study, we have evaluated donepezil hydrochloride, a partial reversible inhibitor of acetylcholinesterase (AChE) clinically used for treating Alzheimer's disease, in combination with procyclidine, used in treatment of Parkinson's disease and schizophrenia, as prophylaxis against intoxication by the nerve agent soman. The results demonstrated significant protective efficacy of donepezil (2.5 mg/kg) combined with procyclidine (3 or 6 mg/kg) when given prophylactically against a lethal dose of soman (1.6 x LD(50)) in Wistar rats. No neuropathological changes were found in rats treated with this combination 48 h after soman intoxication. Six hours after soman exposure cerebral AChE activity and acetylcholine (ACh) concentration was 5% and 188% of control, respectively. The ACh concentration had returned to basal levels 24 h after soman intoxication, while AChE activity had recovered to 20% of control. Loss of functioning muscarinic ACh receptors (17%) but not nicotinic receptors was evident at this time point. The recovery in brain AChE activity seen in our study may be due to the reversible binding of donepezil to the enzyme. Donepezil is well tolerated in humans, and a combination of donepezil and procyclidine may prove useful as an alternative to the currently used prophylaxis against nerve agent intoxication.
Haug
Kristin Huse
KH
Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1112, N-0317 Oslo, Norway. k.h.haug@medisin.uio.no
Myhrer
Trond
T
Fonnum
Frode
F
D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000473:pathology; D003292:Convulsants; D000077265:Donepezil; D004569:Electroencephalography / Q000187:drug effects; D007189:Indans / Q000494:pharmacology*; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011352:Procyclidine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011950:Receptors, Cholinergic / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D012999:Soman
D003292:Convulsants; D007189:Indans; D018727:Muscarinic Antagonists; D018697:Nootropic Agents; D010880:Piperidines; D011950:Receptors, Cholinergic; D000077265:Donepezil; D012999:Soman; D011352:Procyclidine; D000110:Acetylcholinesterase; D000109:Acetylcholine