近日，中国科学院上海药物研究所唐炜及其课题组的最新研究揭示了PDE4抑制剂阿普利米司特通过激活肠道胶质细胞中的Nrf-2信号通路改善TNBS诱导的小鼠肠易激综合征。相关论文于2025年9月1日发表在《中国药理学报》杂志上。

在本研究中，该研究组探讨了PDE4的病理作用和PDE4抑制剂阿普利米司特在IBS中的治疗作用。建立2,4,6-三硝基苯磺酸（TNBS）诱导小鼠肠易激综合征模型，给予阿普利米司特(50毫克/千克,灌胃)治疗7天。治疗后评估肠蠕动和内脏敏感性。在研究结束时，对小鼠实施安乐死，并收集血液和结肠组织进行分析。该研究组发现阿普米司特治疗显著改善了小鼠的IBS症状，这可以通过改善延迟的肠道运动和内脏过敏来证明。

该研究组发现EGCs在IBS小鼠的结肠中被激活。然后研究团队证明了阿普利米司特(10μM)显著抑制TNF-α/IFN-γ刺激的体外大鼠EGC细胞系CRL-2690和原代EGCs的激活，以及EGCs衍生的疼痛介质和炎症因子的分泌，同时改善氧化应激。这些作用依赖于核因子E2相关因子2 （Nrf-2）信号通路的激活，这在Nrf-2敲除的EGCs中得到了验证。这些结果表明，阿普利米司特抑制PDE4通过激活Nrf-2信号通路抑制EGCs的激活，导致疼痛介质和炎症因子的表达减少，同时改善氧化应激，最终缓解IBS。

研究人员表示，肠胶质细胞（EGCs）在肠易激综合征（IBS）的发病机制中起重要作用。磷酸二酯酶-4 （PDE4）是细胞内环磷酸腺苷（cAMP）水解的一种催化酶。PDE4活性的增加促进各种免疫和上皮细胞中促炎细胞因子和趋化因子的过度产生，加剧免疫细胞在炎症组织中的活化和浸润，抑制PDE4已被证明是炎症和自身免疫性疾病的重要策略。

附：英文原文

Title: PDE4 inhibitor apremilast ameliorates TNBS-induced irritable bowel syndrome in mice by activating the Nrf-2 signaling pathway in enteric glial cells

Author: Lu, Yu-hao, Lei, Shu-yue, Yang, Tao, Xu, You-sheng, Wang, Hong-lin, Feng, Chun-lan, Tang, Wei

Issue&Volume: 2025-09-01

Abstract: Enteric glial cells (EGCs) play an important role in the pathogenesis of irritable bowel syndrome (IBS). Phosphodiesterase-4 (PDE4) functions as a catalyzing enzyme targeting hydrolyzation of intracellular cyclic adenosine monophosphate (cAMP). Increased PDE4 activity promotes excessive production of pro-inflammatory cytokines and chemokines in various immune and epithelial cells, exacerbating immune cell activation and infiltration in inflamed tissues, inhibition of PDE4 has been proven to be an important strategy for inflammatory and autoimmune diseases. In this study we investigated the pathological role of PDE4 and the therapeutic effects of a PDE4 inhibitor apremilast in IBS. 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced IBS model was established in mice, the mice were treated with apremilast (50mg/kg, i.g.) for 7 days. After treatment, the intestinal motility and visceral sensitivity were assessed. At the end of the study, the mice were euthanized and the blood and colon tissues were collected for analyses. We showed that apremilast treatment significantly ameliorated IBS symptoms in the mice, evidenced by improvement on delayed intestinal motility and visceral hypersensitivity. We found that EGCs were activated in the colon of IBS mice. We then demonstrated that apremilast (10μM) significantly suppressed TNF-α/IFN-γ stimulated activation of rat EGC cell line CRL-2690 and primary EGCs in vitro, as well as the secretion of EGCs-derived pain mediators and inflammatory factors while ameliorating oxidative stress. These effects depended on the activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling pathway, which was validated in Nrf-2 knockout EGCs. These results suggest that inhibition of PDE4 by apremilast suppresses EGCs activation by activating the Nrf-2 signaling pathway, leading to decreased expression of pain mediators and inflammatory factors while ameliorating oxidative stress, ultimately alleviating IBS.

DOI: 10.1038/s41401-025-01649-w

Source: https://www.nature.com/articles/s41401-025-01649-w