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Effect of S 17092, a Novel Prolyl Endopeptidase Inhibitor, on Substance P and Alpha-Melanocyte-Stimulating Hormone Breakdown in the Rat Brain

Effect of S 17092, a Novel Prolyl Endopeptidase Inhibitor, on Substance P and Alpha-Melanocyte-Stimulating Hormone Breakdown in the Rat Brain

Gaëlle Bellemère, Philippe Morain, Hubert Vaudry, Sylvie Jégou

J Neurochem. 2003 Mar;84(5):919-29.

PMID: 12603817

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP176797265	S 17092		176797-26-5	Price

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