粘膜下神经丛介导恩他卡朋促进结肠分泌的机制研究

Catecholamine refers to dopamine and norepinephrine. Adjust the secretion and absorption of the colonic mucosa. Colonic submucous plexus contains a large number of different functions, secretion- motor neuron. Colonic mucosa of transepithelial ion transport through the release of neurotransmitters (such as: dopamine,ACh,NO,VIP,etc.).Catechol-O-methyltransferase (COMT) is the main metabolizing enzyme of catecholamine. It is also dopamine-degrading enzyme in addition to the central nervous system. Entacapone is considered to be promising new COMT inhibitors. For the treatment of Parkinson's disease have significant effect, but can lead to diarrhea. Our previous studies found that entacapone can promote colonic mucosa secretion of chloride ions. However, the effect can be nerve sodium channel blocker tetrodotoxin blocked. But its pathway of the action, the transmitter/receptor mechanism is unclear. In this study, using a radioimmunoassay method test, through the records of the short-circuit current, the selective ion electrode measurement techniques, and, To investigate mechanism for entacapone induced colonic epithelial Cl- secretion through regulation by the submucosal plexus. To providing theoretical and experimental basis for the diagnosis and treatment of disorders related to intestinal epithelial ion transport.

儿茶酚胺类递质主要包括多巴胺和去甲肾上腺素，参与调节结肠粘膜的分泌与吸收。结肠粘膜下神经丛含有大量功能各异的分泌运动性神经元，通过释放神经递质（如：多巴胺、ACh,NO,VIP等）影响结肠粘膜的跨上皮离子转运。儿茶酚氧位甲基转移酶（catechol-O-methyhransferase，COMT）是儿茶酚胺的主要代谢酶，也是中枢神经系统外多巴胺的主要降解酶。而恩他卡朋是被认为颇有前景的新型的COMT抑制剂，对于治疗帕金森病有明显疗效，但可以导致腹泻。我们前期研究发现：恩他卡朋可以促进结肠粘膜的氯离子分泌，然而该作用可被神经钠通道的阻断剂河豚毒所阻断，但其作用路径、靶点以及参与的递质/受体均不清楚。本研究将通过放射免疫测定法，短路电流记录、选择性离子电极测定技术、分子生物学技术等，深入研究粘膜下神经丛介导恩他卡朋促进结肠上皮离子分泌的调控机制，为肠道上皮离子转运异常的诊治提供理论与实验依据。

儿茶酚胺类递质参与调节结肠粘膜的分泌与吸收。结肠粘膜下神经丛含有大量功能各异的分泌运动性神经元，通过释放儿茶酚胺等多种神经递质影响结肠粘膜的跨上皮离子转运。儿茶酚氧位甲基转移酶（catechol-O-methyhransferase，COMT）是儿茶酚胺的主要代谢酶，也是中枢神经系统外多巴胺的主要降解酶。而恩他卡朋是被认为颇有前景的新型的COMT抑制剂，对于治疗帕金森病有明显疗效，但可以导致腹泻。但其作用路径、靶点等均不清楚。本资助项目针对肠道儿茶酚胺类物质代谢酶及抑制剂对结肠上皮离子分泌的调控机制等进行了探究。发现COMT抑制剂恩他卡朋引起结肠粘膜的短路电流(Isc)改变，能够引起6-OHDA帕金森模型大鼠结肠cAMP依赖性的Cl-分泌；COMT存在于帕金森病模型大鼠结肠的上皮、腺体、细胞核，在肌间神经从也有COMT的表达；单胺氧化酶（MAO）存在于帕金森病模型大鼠结肠的上皮、腺体，在肌间神经从也有MAO的表达，与正常大鼠相比, MAO在帕金森模型鼠中的表达要低于正常鼠；恩他卡朋以剂量依赖性的方式抑制帕金森大鼠结肠纵行肌的收缩。以上实验结果为帕金森肠道紊乱患者，以及肠道上皮离子转运异常的诊断和药物治疗靶点的开发提供了理论与实验依据。