title: N1phenethyl-norcymserine, a selective butyrylcholinesterase inhibitor, increases acetylcholine release in rat cerebral cortex: a comparison with donepezil and rivastigmine.
abstract: The effects of (-)-N(1)phenethyl-norcymserine (PEC, 5 mk/kg, i.p.) on acetylcholine release and cholinesterase activity in the rat cerebral cortex were compared with those of donepezil (1 mg/kg, i.p.), a selective acetylcholinesterase inhibitor, and rivastigmine (0.6 mg/kg, i.p.), an inhibitor of acetylcholinesterase and butyrylcholinesterase. Acetylcholine extracellular levels were measured by microdialysis coupled with HPLC; acetylcholinesterase and butyrylcholinesterase activity were measured with colorimetric and radiometric methods. It was found that comparable 2-3 fold increases in cortical extracellular acetylcholine level, calculated as areas under the curve, followed the administration of the three drugs at the doses used. At the peak of acetylcholine increase, a 27% acetylcholinesterase inhibition and no butyrylcholinesterase inhibition was found after donepezil (1 mg/kg, i.p) administration. At the same time point, rivastigmine (0.6 mg/kg, i.p.) inhibited acetylcholinesterase by 40% and butyrylcholinesterase by 25%. After PEC (5 mg/kg, i.p.) administration, there was a 39% butyrylcholinesterase inhibition and no effect on acetylcholinesterase. Since in the present study it was also confirmed that in the brain butyrylcholinesterase activity is only about 10% of acetylcholinesterase activity, it is surprising that its partial inhibition is sufficient to increase extracellular acetylcholine levels. The importance of butyrylcholinesterase as a "co-regulator" of synaptic acetylcholine levels should thus be reconsidered.
authors.affiliation: Department of Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cerbai
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Giovannini
authors.forename: Claudia
authors.initials: C
authors.lastname: Melani
authors.forename: Albert
authors.initials: A
authors.lastname: Enz
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pepeu
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D007189:Indans / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D013058:Mass Spectrometry; D017551:Microdialysis; D048448:Phenylcarbamates / Q000378:metabolism / Q000494:pharmacology*; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000068836:Rivastigmine
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; C525643:N(1)-phenethylnorcymserine; D048448:Phenylcarbamates; D010880:Piperidines; D000077265:Donepezil; D010830:Physostigmine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D000068836:Rivastigmine