School of life sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University Dalian, PR China.
Front Pharmacol. 2011 Sep 27;2:52. doi: 10.3389/fphar.2011.00052. eCollection 2011.
Mutations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) cause lethal hereditary disease CF that involves extensive destruction and dysfunction of serous epithelium. Possible pharmacological therapy includes correction of defective intracellular processing and abnormal channel gating. In a previous study, we identified five natural coumarin potentiators of ΔF508-CFTR including osthole, imperatorin, isopsoralen, praeruptorin A, and scoparone. The present study was designed to determine the activity of these coumarine compounds on CFTR activity in animal tissues as a primary evaluation of their therapeutic potential. In the present study, we analyzed the affinity of these coumarin potentiators in activating wild-type CFTR and found that they are all potent activators. Osthole showed the highest affinity with K(d) values <50 nmol/L as determined by Ussing chamber short-circuit current assay. Stimulation of rat colonic mucosal secretion by osthole was tested by the Ussing chamber short-circuit current assay. Osthole reached maximal activation of colonic Cl(-) secretion at 5 μmol/L. Stimulation of mouse tracheal mucosal secretion was analyzed by optical measurement of single gland secretion. Fluid secretion rate of tracheal single submucosal gland stimulated by osthole at 10 μmol/L was three-fold more rapid than that in negative control. In both cases the stimulated secretions were fully abolished by CFTR(inh)-172. In conclusion, the effective stimulation of Cl(-) and fluid secretion in colonic and tracheal mucosa by osthole suggested the therapeutic potential of natural coumarin compounds for the treatment of CF and other CFTR-related diseases.
囊性纤维化跨膜电导调节因子 (CFTR) 的突变导致致命遗传性疾病 CF，涉及浆液上皮的广泛破坏和功能障碍。可能的药理学治疗包括纠正有缺陷的细胞内处理和异常通道门控。在之前的研究中，我们鉴定了五种天然香豆素化合物作为 ΔF508-CFTR 的增强剂，包括蛇床子素、欧前胡素、异补骨脂素、白芷素 A 和花椒素。本研究旨在确定这些香豆素化合物在动物组织中对 CFTR 活性的活性，作为其治疗潜力的初步评估。在本研究中，我们分析了这些香豆素增强剂对激活野生型 CFTR 的亲和力，发现它们都是有效的激活剂。蛇床子素表现出最高的亲和力，用 Ussing 室短路电流测定法测定的 K(d) 值<50 nmol/L。通过 Ussing 室短路电流测定法检测蛇床子素对大鼠结肠黏膜分泌的刺激作用。蛇床子素在 5 μmol/L 时达到最大激活结肠 Cl(-)分泌的作用。通过光学测量单个腺体分泌分析鼠气管黏膜分泌的刺激作用。在 10 μmol/L 时，蛇床子素刺激的气管单个黏膜下腺的分泌速率比阴性对照快三倍。在这两种情况下，CFTR(inh)-172 完全消除了刺激的分泌。总之，蛇床子素有效刺激结肠和气管黏膜的 Cl(-)分泌和液体分泌，提示天然香豆素化合物在治疗 CF 和其他 CFTR 相关疾病方面具有治疗潜力。
