title: Effect of S 17092, a novel prolyl endopeptidase inhibitor, on substance P and alpha-melanocyte-stimulating hormone breakdown in the rat brain.
abstract: In the present study, we have investigated the effects of a novel prolyl endopeptidase (EC 3.4.21.26, PEP) inhibitor, compound S 17092, on substance P (SP) and alpha-melanocyte-stimulating hormone (alpha-MSH) metabolism in the rat brain. In vitro experiments revealed that S 17092 inhibits in a dose-dependent manner PEP activity in rat cortical extracts (IC50 = 8.3 nm). In addition, S 17092 totally abolished the degradation of SP and alpha-MSH induced by bacterial PEP. In vivo, a significant decrease in PEP activity was observed in the medulla oblongata after a single oral administration of S 17092 at doses of 10 and 30 mg/kg (-78% and -82%, respectively) and after chronic oral treatment with S 17092 at doses of 10 and 30 mg/kg per day (-75% and -88%, respectively). Concurrently, a single administration of S 17092 (30 mg/kg) caused a significant increase in SP- and alpha-MSH-like immunoreactivity (LI) in the frontal cortex (+41% and +122%, respectively) and hypothalamus (+84% and +49%, respectively). In contrast, chronic treatment with S 17092 did not significantly modify SP- and alpha-MSH-LI in the frontal cortex and hypothalamus. Collectively, the present results show that S 17092 elevates SP and alpha-MSH concentrations in the rat brain by inhibiting PEP activity. These data suggest that the effect of S 17092 on memory impairment can be accounted for, at least in part, by inhibition of catabolism of promnesic neuropeptides such as SP and alpha-MSH.
authors.affiliation: European Institute for Peptide Research (IFRMP23), Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U 413, CNRS, University of Rouen, 76821 Mont-Saint-Aignan, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Bellemère
authors.forename: Philippe
authors.initials: P
authors.lastname: Morain
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
authors.forename: Sylvie
authors.initials: S
authors.lastname: Jégou
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001681:Biological Assay; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005417:Flavobacterium / Q000378:metabolism; D005625:Frontal Lobe / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D007031:Hypothalamus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008526:Medulla Oblongata / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D000085822:Prolyl Oligopeptidases; D011480:Protease Inhibitors / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013373:Substance P / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines; D000521:alpha-MSH / Q000378:metabolism*
chemical_list: D007211:Indoles; D011480:Protease Inhibitors; C118986:S 17092-1; D013844:Thiazoles; D053778:Thiazolidines; D013373:Substance P; D000521:alpha-MSH; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases