The combination of donepezil and procyclidine protects against soman-induced seizures in rats
Journal Article
·
· Toxicology and Applied Pharmacology
- Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1112, N-0317 Oslo (Norway)
- Protection Division, Norwegian Defence Research Establishment, Kjeller (Norway)
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 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 (1.6x LD{sub 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.
- OSTI ID:
- 20976906
- Journal Information:
- Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 220; ISSN TXAPA9; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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