title: Inhibition of prolyl oligopeptidase by KYP-2047 fails to increase the extracellular neurotensin and substance P levels in rat striatum.
abstract: Prolyl oligopeptidase (PREP, EC 3.4.21.26) hydrolyzes neuropeptides, such as neurotensin and substance P in vitro, but its importance in the in vivo metabolism of these peptides has not been proved. This is the first report where intracerebral microdialysis combined with highly sensitive radioimmunoassay has been used to investigate the effect of PREP inhibition on the brain extracellular peptide levels in conscious rats. We show that PREP inhibition by KYP-2047 (50μmol/kg=17mg/kg, intraperitoneally, that effectively inhibits PREP in the brain), has no effect on the neurotensin and substance P levels in the striatum extracellular space. This provides a further piece of evidence in support of the proposition that PREP is not significantly responsible for the in vivo cleavage of substance P or neurotensin, and that occasional positive cognitive effects associated with some PREP inhibitors are not mediated through elevated extracellular levels of these peptides. Direct regulation of peptide processing by PREP is not likely because the enzyme is located intracellularly and the peptide substrates are mostly extracellular.
authors.affiliation: School of Pharmacy, University of Eastern Finland, Faculty of Health Sciences, P.O. Box 1627, FI-70211 Kuopio, Finland. Aaro.Jalkanen@uef.fi
authors.forename: Aaro J
authors.initials: AJ
authors.lastname: Jalkanen
authors.forename: Katja
authors.initials: K
authors.lastname: Savolainen
authors.forename: Markus M
authors.initials: MM
authors.lastname: Forsberg
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology*; D005110:Extracellular Space / Q000187:drug effects / Q000201:enzymology; D008297:Male; D017551:Microdialysis / Q000379:methods; D009496:Neurotensin / Q000378:metabolism*; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D000085822:Prolyl Oligopeptidases; D011863:Radioimmunoassay / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013373:Substance P / Q000378:metabolism*
chemical_list: C551540:4-phenylbutanoyl-prolylcyanopyrrolidine; D015842:Serine Proteinase Inhibitors; D013373:Substance P; D009496:Neurotensin; D011392:Proline; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases