title: Prolyl oligopeptidase inhibition decreases extracellular acetylcholine levels in rat hippocampus and prefrontal cortex.
abstract: Several investigative prolyl oligopeptidase (PREP) inhibitors have been shown to improve learning and memory in various preclinical trials but the mechanism of action behind these effects remains unclear. Since hippocampal and cortical acetylcholine (ACh) is known to play an important role in cognitive processes, the effects of two potent PREP inhibitors, JTP-4819 and KYP-2047, on extracellular ACh levels in hippocampus and medial prefrontal cortex were assessed using in vivo microdialysis. Conscious rats were treated with a single dose (15 or 50μmol/kg i.p.) of JTP-4819, KYP-2047 or vehicle, and extracellular ACh levels were monitored for 5h after treatment. In hippocampus, KYP-2047 had no significant effect on the ACh levels, although a trend towards decreased levels was observed at the higher dose. JTP-4819 had no significant effect on the hippocampal ACh levels at the lower dose (15μmol/kg), but the higher dose (50μmol/kg) significantly decreased ACh levels in hippocampus by about 25%. In cortex, the smaller dose (15μmol/kg) of KYP-2047 decreased ACh levels maximally by 25%, and a similar (ns) effect was also observed after the higher dose. JTP-4819 had no effect at the lower dose, but the higher dose decreased ACh levels maximally by about 30%. In conclusion, the present results suggest that the cognition-enhancing effects of investigative PREP inhibitors are not due to enhanced cholinergic transmission in hippocampus or cortex.
authors: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland. Electronic address: Aaro.Jalkanen@uef.fi.
authors: Aaro J
authors: AJ
authors: Jalkanen
authors: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors: Juuso V
authors: JV
authors: Leikas
authors: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors: Markus M
authors: MM
authors: Forsberg
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D000085822:Prolyl Oligopeptidases; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
chemical_list: C551540:4-phenylbutanoyl-prolylcyanopyrrolidine; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D011392:Proline; C094211:JTP 4819; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases; D000109:Acetylcholine
keywords: Acetylcholine; Cortex; Hippocampus; JTP-4819; KYP-2047; Prolyl oligopeptidase