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Celecoxib Exerts a Therapeutic Effect Against Demyelination by Improving the Immune and Inflammatory
Peipei Cao1, Hao Zhang2, Huiling Meng1
1Nankai University School of Medicine, Tianjin, People's Republic of China.
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.
Insights
Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, promotes myelin sheath repair in zebrafish by reducing inflammation and apoptosis. This offers a potential therapeutic strategy for demyelinating diseases.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Demyelinating diseases lack effective treatments.
- Overexpression of cyclooxygenase-2 (COX-2) is observed in demyelinating lesions.
- Targeting COX-2 presents a potential therapeutic avenue for remyelination.
Purpose of the Study:
- To investigate the therapeutic potential of celecoxib, a selective COX-2 inhibitor, in a zebrafish model of demyelination.
- To evaluate the effect of celecoxib on myelin sheath regeneration and underlying mechanisms.
Main Methods:
- Celecoxib biotoxicity was assessed in zebrafish embryos.
- A demyelination model was induced using metronidazole in transgenic fish.
- Myelin regeneration and cellular mechanisms were analyzed using immunohistochemistry, flow cytometry, Western blot, qPCR, and behavioral tests.
Main Results:
- Celecoxib demonstrated low in vivo toxicity.
- Treatment with celecoxib significantly increased oligodendrocyte numbers and restored myelin sheath structure.
- Locomotor function improved significantly, and specific gene expressions related to inflammation and apoptosis were modulated.
Conclusions:
- COX-2 inhibition by celecoxib promotes microglia/macrophage M2 phenotype transformation.
- Celecoxib treatment improves the inflammatory microenvironment and suppresses apoptosis.
- These effects contribute to the therapeutic efficacy of celecoxib against demyelination.
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