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.



中文翻译：

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塞来昔布通过改善免疫和炎症微环境对脱髓鞘产生治疗作用

背景：髓鞘可能被遗传和/或环境因素破坏，导致脱髓鞘疾病，目前缺乏有效的治疗方法。最近，在患者和动物模型的脱髓鞘病变中检测到环氧合酶 2 (COX-2) 过表达，为促进内源性髓鞘再生开辟了一条途径。本研究的目的是研究塞来昔布（一种选择性 COX-2 抑制剂）对斑马鱼模型脱髓鞘的治疗作用。
方法：塞来昔布的生物毒性在斑马鱼胚胎上进行了评估。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施用塞来昔布。通过免疫组化、流式细胞术、Western印迹分析、定量实时聚合酶链反应和行为学测试探索髓鞘的再生及其潜在机制。
结果：塞来昔布具有低体内毒性。甲硝唑诱导建立了稳定实用的脱髓鞘模型。塞来昔布治疗后，少突胶质细胞数量显着增加，髓鞘同心结构再次出现。运动能力显着提高，接近生理水平。arg1、mrc1、il-10和il-4的表达上调，而il-1β、il-12、tnf-α、il-6、caspase-3和caspase-7的表达下调。
结论：抑制COX-2有助于小胶质细胞/巨噬细胞从M1表型向M2表型转化，改善炎症微环境，抑制caspase依赖性细胞凋亡，从而发挥抗脱髓鞘作用。