Effect of prolyl endopeptidase inhibition on arginine-vasopressin and thyrotrophin-releasing hormone catabolism in the rat brain
Effect of prolyl endopeptidase inhibition on arginine-vasopressin and thyrotrophin-releasing hormone catabolism in the rat brain
复制标题
DOI：
10.1111/j.1365-2826.2005.01308.x
复制
发表时间：
2005-05-01
影响因子：
3.2
通讯作者：
Jégou, S
中科院分区：
文献类型：
--
作者：
Bellemère, G;Vaudry, H;Jégou, S
化合物S 17092是脯氨酰内肽酶（EC 3.4.21.26，PEP）的有效和选择性抑制剂，其对于治疗与神经变性疾病相关的记忆障碍可能具有治疗价值。本实验观察了S 17092对大鼠脑内促甲状腺激素释放激素（TRH）和精氨酸加压素（AVP）的抑制作用。在体外，细菌PEP水解TRH和AVP，10（-5）M S 17092几乎完全阻止了这两种肽的分解。在体内，S 17092单次经口给药引起大脑皮层中TRH样免疫反应性（TRH-LI）显著增加（10 mg/kg剂量为+63%，30 mg/kg剂量为+72%），以及海马中AVP-LI显著增加（30 mg/kg剂量为+54%），但不影响杏仁核中的TRH-LI和大脑皮层中的AVP-LI。长期给予S 17092（10或30 mg/kg/天）导致大脑皮层中THR-LI显著增加（分别为+55%和+56%），但未改变海马和大脑皮层中的AVP-LI。这些结果表明，选择性PEP抑制剂S 17092增加大鼠脑的离散区域中的TRH和AVP含量。目前的数据表明，S 17092的促记忆和抗记忆作用可以解释，至少部分是通过PEP阻断AVP和TRH降解。
Compound S 17092 is a potent and selective inhibitor of prolyl endopeptidase (EC 3.4.21.26, PEP) that may be of therapeutic value for the treatment of memory impairment associated with neurodegenerative diseases. In the present study, we investigated the effects of S 17092 on the catabolism of the promnesic neuropeptides thyrotrophin-releasing hormone (TRH) and arginine-vasopressin (AVP) in the rat brain. In vitro, bacterial PEP hydrolysed both TRH and AVP, and the breakdown of the two peptides was almost completely prevented by 10(-5) M S 17092. In vivo, a single oral administration of S 17092 provoked a significant increase in TRH-like immunoreactivity (TRH-LI) in the cerebral cortex (+63% for a 10 mg/kg dose and +72% for a 30 mg/kg dose), as well as AVP-LI in the hippocampus (+54% for a 30 mg/kg dose), but did not affect TRH-LI in the amygdala nor AVP-LI in the cerebral cortex. Chronic administration of S 17092 (10 or 30 mg/kg daily) lead to a significant increase in THR-LI in the cerebral cortex (+55% and +56%, respectively), but did not modify AVP-LI in the hippocampus, nor in the cerebral cortex. These results show that the selective PEP inhibitor S 17092 increases TRH and AVP content in discrete regions of the rat brain. The present data suggest that the promnesic and antiamnesic effects of S 17092 can be accounted for, at least in part, by blockage of AVP and TRH degradation by PEP.