title: Effects on cholinergic markers in rat brain and blood after short and prolonged administration of donepezil.
abstract: Donepezil is a selective inhibitor of acetylcholinesterase (AChE) clinically used for treating Alzheimer's disease. Cholinergic effects after short-term exposure of donepezil (up to 12 h) have been extensively studied in rats, but few have addressed the potential long-term effects. After 14 days administration (1x3 mg/kg, decapitation 4 h after the last injection) the cerebral acetylcholine level was increased by 35% and the AChE activity was decreased by 66% and 32% in brain and blood, respectively. No change was detected in choline acetyltransferase activity, or the levels of vesicular acetylcholine transporter, choline transporter, or muscarinic receptors. Expression of various cholinergic genes was unaffected. Preliminary results of AChE activity in human blood showed 60-97% and 43-89% of pre-exposed level after one and three days of donepezil administration (5 mg daily), respectively. In conclusion, donepezil exposure in rats at doses that do not inhibit brain AChE continuously during the day, will not lead to tolerance development.
authors.affiliation: 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
authors.forename: Kristin Huse
authors.initials: KH
authors.lastname: Haug
authors.forename: Inger Lise
authors.initials: IL
authors.lastname: Bogen
authors.forename: Harald
authors.initials: H
authors.lastname: Osmundsen
authors.forename: Ivar
authors.initials: I
authors.lastname: Walaas
authors.forename: Frode
authors.initials: F
authors.lastname: Fonnum
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000368:Aged; D000818:Animals; D001831:Body Temperature; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000077265:Donepezil; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010880:Piperidines / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011950:Receptors, Cholinergic / Q000187:drug effects* / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D011950:Receptors, Cholinergic; D000077265:Donepezil; D000110:Acetylcholinesterase; D000109:Acetylcholine