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Suppression of TLR4/MyD88/TAK1/NF-κB/COX-2 Signaling Pathway in the Central Nervous System by Bexarotene, a Selective RXR Agonist, Prevents Hyperalgesia in the Lipopolysaccharide-Induced Pain Mouse Model

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Abstract

A selective RXR agonist, bexarotene, has been shown to have anti-inflammatory, anti-nociceptive, and neuroprotective effects in several models of numerous neurological diseases characterized by systemic inflammation. The mechanisms underlying these effects remains unknown. To elucidate these mechanisms, we investigated whether the TLR4/MyD88/TAK1/NF-κB/COX-2 signaling pathway in the CNS mediates the effect of bexarotene to prevent hyperalgesia in the LPS-induced inflammatory pain mouse model. The reaction time to thermal stimuli within 30 s was evaluated by the hot plate test in male mice treated with saline, LPS (10 mg/kg), DMSO, and/or bexarotene (0.1, 1, 3, or 10 mg/kg) after 6 h. The latency to the thermal stimulus (18.11 ± 1.36 s) in the LPS-treated mice was significantly decreased by 30% compared with saline-treated mice (25.84 ± 1.99 s). Treatment with bexarotene only at a dose of 10 mg/kg showed a significant increase in the latency by 22.49 ± 1.00 s compared with LPS-treated mice. Bexarotene also prevented the reduction in RXRα protein expression associated with a rise in the expression of TLR4, MyD88, phosphorylated TAK1, NF-κB p65, phosphorylated NF-κB p65, COX-2, and IL-1β proteins, in addition to COX-2 activity and levels of PGE2 and IL-1β in the brains and spinal cords of the LPS-treated animals. Likely, decreased activity of TLR4/MyD88/TAK1/NF-κB/COX-2 signaling pathway in addition to increased pro-inflammatory cytokine formation in the CNS of mice participates in the protective effect of bexarotene against hyperalgesia induced by LPS.

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Acknowledgements

This work was supported by grants from Mersin University for 2018-1-TP3-2814 and The Scientific and Technological Research Council of Turkey for SBAG-217S235. The results of this study were included in the Doctorate Thesis of Pharm. M.S. Sefika Pinar Senol.

Funding

This work was supported by grants from Mersin University for 2018–1-TP3–2814 and The Scientific and Technological Research Council of Turkey for SBAG-217S235.

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  1. Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey

    Sefika Pinar Senol, Meryem Temiz-Resitoglu, Demet Sinem Guden, Ayse Nihal Sari, Seyhan Sahan-Firat & Bahar Tunctan

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Contributions

BT and SSPS conceptualized and conceived the research design, carried out the experiments, analyzed the data, and drafted the manuscript. MTR and DSG participated in the experiments and revised the contents of the manuscript. SSF and ANS contributed to the finalizing of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Bahar Tunctan.

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All animal experiments were authorized by the Mersin University Experimental Animals Local Ethics Committee (Approval Date: April 16, 2018; Decision Number: 2018/20) and carried out according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Senol, S.P., Temiz-Resitoglu, M., Guden, D.S. et al. Suppression of TLR4/MyD88/TAK1/NF-κB/COX-2 Signaling Pathway in the Central Nervous System by Bexarotene, a Selective RXR Agonist, Prevents Hyperalgesia in the Lipopolysaccharide-Induced Pain Mouse Model. Neurochem Res 46, 624–637 (2021). https://doi.org/10.1007/s11064-020-03197-7

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