Effects on cholinergic markers in rat brain and blood after short and prolonged administration of donepezil.
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.
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
Bogen
Inger Lise
IL
Osmundsen
Harald
H
Walaas
Ivar
I
Fonnum
Frode
F
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
D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D011950:Receptors, Cholinergic; D000077265:Donepezil; D000110:Acetylcholinesterase; D000109:Acetylcholine