艾司氯胺酮调节Nrf2/HO-1信号通路对骨关节炎大鼠镇痛作用的研究-东南大学学报医学版

艾司氯胺酮调节Nrf2/HO-1信号通路对骨关节炎大鼠镇痛作用的研究

单位：安阳市人民医院麻醉科, 河南安阳 455000

分类号：Q95-33;R684.3

出版年·卷·期（页码）：2023·42·第一期（9-15）

摘要：

目的：探讨艾司氯胺酮（S-KET）对骨关节炎（OA）大鼠镇痛作用。方法：随机选择10只大鼠记为假手术组（SH组）；将40只OA造模成功的大鼠随机均分为模型组（Mod组）、L-S-KET组[10 mg·（kg·d）^-1]、M-S-KET组[20 mg·（kg·d）^-1]、H-S-KET组[40 mg·（kg·d）^-1]、H-S-KET+ML385组[40 mg·（kg·d）^-1S-KET+30 mg·（kg·d）^-1Nrf2抑制剂ML385]，每天1次相应腹腔注射，持续7 d。通过机械痛阈实验和热痛阈实验测量机械痛阈值（PWT）和热痛阈值（PWL）；ELISA检测炎症因子和致痛因子水平；HE染色检测软骨组织病理变化情况；Western blotting检测基质金属蛋白酶（MMP）-3、MMP-13以及核因子EZ相关因子2（Nrf2）/血红蛋白氧合酶-1（HO-1）通路蛋白表达。结果：SH组大鼠软骨表面光滑，无任何异常现象，而Mod组大鼠软骨出现糜烂、破坏等现象，软骨细胞数量减少。与SH组相比，Mod组大鼠OARSI评分，白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）水平，MMP-3、MMP-13蛋白水平以及前列腺素E2（PGE2）水平均显著升高（P<0.05），PWT、PWL，Nrf2、HO-1蛋白水平显著降低（P<0.05）；与Mod组相比，L-S-KET组、M-S-KET组、H-S-KET组软骨损伤改善，OARSI评分，IL-1β、TNF-α水平，MMP-3、MMP-13蛋白水平以及PGE2含量均显著下降（P<0.05），PWT、PWL，Nrf2、HO-1蛋白水平显著升高（P<0.05），S-KET具有剂量依赖性；H-S-KET+ML385组软骨损伤情况，炎症因子、通路蛋白水平与Mod组一致。结论：S-KET可能通过调节Nrf2/HO-1信号通路对OA大鼠发挥镇痛作用。

Objective: To investigate the analgesic effect of esketamine(S-KET) on osteoarthritis rats by regulating Nrf2/HO-1 signal pathway. Methods: 10 rats were randomly selected as sham operation group(SH group), and other rats were used to construct the model of osteoarthritis(OA), the rats with successful modeling were randomly divided into Mod group(model group), L-S-KET group(10 mg·kg^-1·d^-1), M-S-KET group(20 mg·kg^-1·d^-1), H-S-KET group(40 mg·kg^-1·d^-1), H-S-KET+ML385 group(40 mg·kg^-1·d^-1 S-KET+30 mg·kg^-1·d^-1 Nrf2 inhibitor ML385), once a day for 7 days, with 10 SD rats in each group. Mechanical pain threshold(PWT) and thermal pain threshold(PWL) were measured by mechanical pain threshold experiment and thermal pain threshold experiment; the levels of inflammatory factors and pain causing factors were detected by ELISA; HE staining was used to detect the pathological changes of cartilage; Western blotting was used to detect the expression of MMP-3, MMP-13 and Nrf2/HO-1 pathway proteins. Results: The cartilage surface of rats in SH group was smooth without any abnormality, while the cartilage of rats in Mod group was eroded and destroyed, and the number of chondrocytes decreased. Compared with SH group, the OARSI score and interleukin-1 β(IL-1 β),tumor necrosis factor-α(TNF-α) levels, matrix metalloproteinase-3(MMP-13) protein levels and prostaglandin E2(PGE2) of rats in Mod group were significantly increased(P<0.05), PWT, PWL values, Nrf2 and HO-1 protein levels decreased greatly(P<0.05); compared with Mod group, the cartilage damage in L-S-KET group, M-S-KET group and H-S-KET group was improved, the OARSI score, IL-1β, TNF-α levels, MMP-3, MMP-13 protein levels and PGE2 content of rats decreased greatly(P<0.05), PWT, PWL values, Nrf2 and HO-1 protein levels increased greatly(P<0.05); S-KET was dose dependent. The cartilage damage, inflammatory factors level and pathway proteins level in H-S-KET+ML385 group were consistent with those in Mod group. Conclusion: S-KET may play an analgesic role in OA rats by regulating Nrf2/HO-1 signal pathway.

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