Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.).
Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania (J.P.R., H.S.E., M.P.D., M.C., A.I.O., S.K.); Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (E.M., C.O.L., A.C.J., B.G.-V.M.); Department of Pathology and Cell Biology, College of Physicians and Surgeons (M.D.G.) and Department of Pediatrics (M.R.), Columbia University, New York, New York; and WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, China (Y.S., C.-C.C.)
J Pharmacol Exp Ther. 2019 Feb;368(2):299-307. doi: 10.1124/jpet.118.252973. Epub 2018 Nov 9.
Abdominal pain represents a significant complaint in patients with irritable bowel syndrome (IBS). While the etiology of IBS is incompletely understood, prior exposure to gastrointestinal inflammation or psychologic stress is frequently associated with the development of symptoms. Inflammation or stress-induced expression of growth factors or cytokines may contribute to the pathophysiology of IBS. Here, we aimed to investigate the therapeutic potential of inhibiting the receptor of glial cell line-derived neurotrophic factor, rearranged during transfection (RET), in experimental models of inflammation and stress-induced visceral hypersensitivity resembling IBS sequelae. In RET-cyan fluorescent protein [(CFP) Ret] mice, thoracic and lumbosacral dorsal root ganglia were shown to express RET, which colocalized with calcitonin gene-related peptide. To understand the role of RET in visceral nociception, we employed GSK3179106 as a potent, selective, and gut-restricted RET kinase inhibitor. Colonic hyperalgesia, quantified as exaggerated visceromotor response to graded pressures (0-60 mm Hg) of isobaric colorectal distension (CRD), was produced in multiple rat models induced 1) by colonic irritation, 2) following acute colonic inflammation, 3) by adulthood stress, and 4) by early life stress. In all the rat models, RET inhibition with GSK3179106 attenuated the number of abdominal contractions induced by CRD. Our findings identify a role for RET in visceral nociception. Inhibition of RET kinase with a potent, selective, and gut-restricted small molecule may represent a novel therapeutic strategy for the treatment of IBS through the attenuation of post-inflammatory and stress-induced visceral hypersensitivity.
腹痛是肠易激综合征（IBS）患者的主要症状。尽管 IBS 的病因尚未完全阐明，但先前的胃肠道炎症或心理压力暴露通常与症状的发展有关。炎症或应激诱导的生长因子或细胞因子的表达可能与 IBS 的病理生理学有关。在这里，我们旨在研究抑制胶质细胞系衍生的神经营养因子受体（RET）在类似于 IBS 后遗症的炎症和应激诱导内脏敏感性模型中的治疗潜力。在 RET-青色荧光蛋白（CFP）Ret 小鼠中，胸腰椎背根神经节表达 RET，其与降钙素基因相关肽共定位。为了了解 RET 在内脏疼痛感知中的作用，我们使用 GSK3179106 作为一种有效的、选择性的和肠道限制的 RET 激酶抑制剂。通过以下方法在多种大鼠模型中产生结肠超敏反应，量化为等压结直肠扩张（CRD）的分级压力（0-60mmHg）引起的内脏运动反应过度：1）结肠刺激，2）急性结肠炎症后，3）成年期应激，4）生命早期应激。在所有大鼠模型中，GSK3179106 抑制 RET 可减少 CRD 诱导的腹部收缩次数。我们的研究结果确定了 RET 在内脏疼痛感知中的作用。使用有效的、选择性的和肠道限制的小分子抑制 RET 激酶可能代表一种通过减轻炎症后和应激诱导的内脏敏感性来治疗 IBS 的新治疗策略。
