Bellemère Gaëlle, Morain Philippe, Vaudry Hubert, Jégou Sylvie
European Institute for Peptide Research (IFRMP23), Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U 413, CNRS, University of Rouen, 76821 Mont-Saint-Aignan, France.
J Neurochem. 2003 Mar;84(5):919-29. doi: 10.1046/j.1471-4159.2003.01536.x.
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.
在本研究中，我们调查了一种新型脯氨酰内肽酶（EC 3.4.21.26，PEP）抑制剂化合物S 17092对大鼠脑内P物质（SP）和α-黑素细胞刺激素（α-MSH）代谢的影响。体外实验表明，S 17092以剂量依赖性方式抑制大鼠皮质提取物中的PEP活性（IC50 = 8.3 nM）。此外，S 17092完全消除了细菌PEP诱导的SP和α-MSH的降解。在体内，单次口服剂量为10和30 mg/kg的S 17092后，延髓中的PEP活性显著降低（分别为-78%和-82%），以及每天口服剂量为10和30 mg/kg的S 17092进行慢性治疗后（分别为-75%和-88%）。同时，单次给予S 17092（30 mg/kg）导致额叶皮质中SP和α-MSH样免疫反应性（LI）显著增加（分别为+41%和+122%）以及下丘脑（分别为+84%和+49%）。相比之下，用S 17092进行慢性治疗并未显著改变额叶皮质和下丘脑中的SP和α-MSH-LI。总体而言，目前的结果表明，S 17092通过抑制PEP活性提高大鼠脑中SP和α-MSH的浓度。这些数据表明，S 17092对记忆障碍的影响至少部分可以通过抑制诸如SP和α-MSH等促记忆神经肽的分解代谢来解释。
