Celecoxib Exerts a Therapeutic Effect Against Demyelination by Improving the Immune and Inflammatory Microenvironments.
Celecoxib Exerts a Therapeutic Effect Against Demyelination by Improving the Immune and Inflammatory Microenvironments.
复制标题
塞来昔布通过改善免疫和炎症微环境发挥抗脱髓鞘作用
DOI：
10.2147/jir.s282128
复制
发表时间：
2020
影响因子：
4.5
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Cao P;Zhang H;Meng H;Cheng Y;Xu H;Zang S;Li Z;Cui J;Li Y
背景髓鞘可被遗传和/或环境因素损伤，导致脱髓鞘疾病，缺乏有效的治疗方法。最近，在脱髓鞘病变的患者和动物模型中检测到环氧化酶-2（考克斯-2）过表达，为促进内源性髓鞘再生开辟了途径。本研究的目的是研究塞来昔布，一种选择性考克斯-2抑制剂，对斑马鱼模型脱髓鞘的治疗作用。方法用斑马鱼胚胎评价塞来昔布的生物毒性。甲硝唑用于消耗Tg（mbp：nfsB-egfp）转基因鱼中的少突胶质细胞。然后在幼虫和成虫中给予塞来昔布。通过免疫组化、流式细胞术、Western印迹分析、实时定量聚合酶链反应和行为学测试来探讨髓鞘的再生及其机制。结果塞来昔布体内毒性低。采用甲硝唑诱导法建立了稳定实用的脱髓鞘模型。塞来昔布治疗后，少突胶质细胞的数量显着增加，髓鞘的同心圆结构重新出现。运动能力明显提高，接近生理水平。arg 1、mrc 1、il-10、il-4表达上调，il-1β、il-12、tnf-α、il-6、caspase-3、caspase-7表达下调。结论抑制考克斯-2可促进小胶质细胞/巨噬细胞由M1型向M2型转化，改善炎症微环境，抑制caspase依赖性凋亡，从而发挥抗脱髓鞘作用。
Background The myelin sheath can be damaged by genetic and/or environmental factors, leading to demyelinating diseases, for which effective treatments are lacking. Recently, cyclooxygenase-2 (COX-2) overexpression was detected in demyelinating lesions both in patients and animal models, opening an avenue for promoting endogenous remyelination. The aim of this study was to investigate the therapeutic effect of celecoxib, a selective COX-2 inhibitor, against demyelination in a zebrafish model. Methods The biotoxicity of celecoxib was evaluated on zebrafish embryos. Metronidazole was used to deplete the oligodendrocytes in Tg (mbp:nfsB-egfp) transgenic fish. Celecoxib was then administered both in larvae and adults. The regeneration of the myelin sheath and the underlying mechanisms were explored by immunohistochemistry, flow cytometry, Western blot analysis, quantitative real-time polymerase chain reaction, and behavioral test. Results Celecoxib had low in vivo toxicity. A stable and practical demyelination model was established by metronidazole induction. Following celecoxib treatment, the number of oligodendrocytes was increased significantly and the concentric structure of the myelin sheath reappeared. The locomotor ability was notably improved and was close to its physiological levels. The expression of arg1, mrc1, il-10, and il-4 was upregulated, while that of il-1β, il-12, tnf-α, il-6, caspase-3 and caspase-7 was downregulated. Conclusion Inhibition of COX-2 contributed to the transformation of microglia/macrophages from the M1 to the M2 phenotype, improved the inflammatory microenvironment, and suppressed caspase-dependent apoptosis, thus exerting a therapeutic effect against demyelination.