Di Salvo Clelia, D'Antongiovanni Vanessa, Benvenuti Laura, Fornai Matteo, Valdiserra Giulia, Natale Gianfranco, Ryskalin Larisa, Lucarini Elena, Mannelli Lorenzo Di Cesare, Ghelardini Carla, Colucci Rocchina, Haskó György, Pellegrini Carolina, Antonioli Luca
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
J Drug Target. 2024 Sep;32(8):953-963. doi: 10.1080/1061186X.2024.2367563. Epub 2024 Jul 2.
Nowadays, the pharmacological management of visceral hypersensitivity associated with colitis is ineffective. In this context, targeting purinergic P2X4 receptor (P2X4R), which can modulate visceral pain transmission, could represent a promising therapeutic strategy. Herein, we tested the pain-relieving effect of two novel and selective P2X4R antagonists (NC-2600 and NP-1815-PX) in a murine model of DNBS-induced colitis and investigated the mechanisms underlying their effect. Tested drugs and dexamethasone (DEX) were administered orally, two days after colitis induction. Treatment with tested drugs and DEX improved tissue inflammatory parameters (body weight, spleen weight, macroscopic damage, TNF and IL-1β levels) in DNBS-rats. In addition, NC-2600 and NP-1815-PX attenuated visceral pain better than DEX and prevented the reduction of occludin expression. In studies, treatment of CaCo2 cells with supernatant from THP-1 cells, previously treated with LPS plus ATP, reduced the expression of tight junctions protein. By contrast, CaCo2 cells treated with supernatant from THP-1 cells, previously incubated with tested drugs, counteracted the reduction of tight junctions due to the inhibition of P2X4R/NLRP3/IL-1β axis. In conclusion, these results suggest that the direct and selective inhibition of P2X4R represents a viable approach for the management of visceral pain associated with colitis NLRP3/IL-1β axis inhibition.
如今，与结肠炎相关的内脏超敏反应的药物治疗效果不佳。在此背景下，靶向嘌呤能P2X4受体（P2X4R），其可调节内脏痛觉传递，可能是一种有前景的治疗策略。在此，我们在二硝基苯磺酸（DNBS）诱导的结肠炎小鼠模型中测试了两种新型选择性P2X4R拮抗剂（NC - 2600和NP - 1815 - PX）的止痛效果，并研究了其作用的潜在机制。在结肠炎诱导两天后，口服给予受试药物和地塞米松（DEX）。受试药物和DEX治疗改善了DNBS诱导大鼠的组织炎症参数（体重、脾脏重量、宏观损伤、TNF和IL - 1β水平）。此外，NC - 2600和NP - 1815 - PX比DEX更能减轻内脏疼痛，并防止紧密连接蛋白occludin表达的降低。在研究中，用先前用脂多糖（LPS）加ATP处理的THP - 1细胞的上清液处理CaCo2细胞，降低了紧密连接蛋白的表达。相比之下，用先前与受试药物孵育的THP - 1细胞的上清液处理CaCo2细胞，可抵消由于P2X4R/NLRP3/IL - 1β轴抑制导致的紧密连接减少。总之，这些结果表明，直接和选择性抑制P2X4R是管理与结肠炎相关的内脏疼痛的一种可行方法，其通过抑制NLRP3/IL - 1β轴实现。
