Rasagiline, an inhibitor of MAO-B, decreases colonic motility through elevating colonic dopamine content
Rasagiline, an inhibitor of MAO-B, decreases colonic motility through elevating colonic dopamine content
复制标题
雷沙吉兰是一种 MAO-B 抑制剂，通过提高结肠多巴胺含量来降低结肠运动
DOI：
10.1111/nmo.13390
复制
发表时间：
2018-11-01
影响因子：
3.5
通讯作者：
Zhu, J. -X.
中科院分区：
文献类型：
--
作者：
Liu, C. -Z.;Zhang, X. -L.;Zhu, J. -X.
多巴胺(DA)是肠道运动的负性调节剂。单胺氧化酶-B(MAO-B)是降解DA的一种重要代谢酶。雷沙吉兰是一种不可逆转的MAO-B抑制剂，由于其神经保护作用和增加中枢DA而被用于治疗帕金森病。但目前尚不清楚MAO-B是否存在于结肠中，雷沙吉兰增加结肠DA，从而影响结肠运动。方法采用免疫组织化学、Western blotting、酶活性测定、结肠动力记录、肠道传输试验和高效液相-电化学检测等方法。大鼠口服雷沙吉兰4周后，离体肠动力明显降低，但可被多巴胺D-1受体拮抗剂SCH-23390逆转。雷沙吉兰治疗组大鼠结肠肌层MAO-B活性降低，DA含量增加，但D-1、D-2受体、MAO-A、MAO-B蛋白表达及5-羟色胺和去甲肾上腺素含量无明显变化。尽管MAO-B活性受到明显抑制，但雷沙吉兰急性给药对大鼠体外结肠运动和结肠DA水平无明显影响。结论：单胺氧化酶-B在大鼠和人结肠肌层包括肌间神经丛中含量丰富。长期应用雷沙吉兰可增加结肠DA，从而抑制结肠运动，提示结肠MAO-B可能是治疗结肠运动障碍的潜在药物靶点。
BackgroundDopamine (DA) is a negative modulator of gut motility. Monoamine oxidase-B (MAO-B) is an important metabolic enzyme degrading DA. Rasagiline, an irreversible MAO-B inhibitor, is used to treat Parkinson's disease because of its neuroprotective effect and increasing central DA. However, it is unclear whether MAO-B exists in the colon and rasagiline increases colonic DA, thereby affecting colonic motility.MethodsKey ResultsImmunohistochemistry, western blotting, enzyme activity assay, colonic motility recording, gut transit test, and high-performance liquid chromatography-electrochemical detection were employed in this study.Monoamine oxidase-B was distributed in the colonic muscular layers including neurons and glias of rat and human. When oral treatment of rats with rasagiline for 4weeks, in vitro colonic motility was significantly reduced, but it was greatly reversed by SCH-23390, an antagonist of DA D-1 receptor. The rasagiline-treated rats also manifested decreased MAO-B activity and increased DA content in the colonic muscular layer, but no alterations were detected in the protein expressions of D-1 and D-2 receptors, and MAO-A and MAO-B, as well as in the content of 5-hydroxytryptamine and noradrenaline. Moreover, acute administration of rasagiline did not affect the colonic motility in vitro and the colonic DA level in rats, although MAO-B activity was significantly inhibited.Conclusions & InferencesMonoamine oxidase-B is abundant in the colonic muscular layer including myenteric plexus of rat and human. Long-term administration of rasagiline can increase colonic DA thereby inhibiting colonic motility, suggesting that colonic MAO-B could be a potential drug target for colonic dysmotility.