Dergi makalesi Açık Erişim

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

2021    Senol, Sefika Pinar; Temiz-Resitoglu, Meryem; Guden, Demet Sinem; Sari, Ayse Nihal; Sahan-Firat, Seyhan; Tunctan, Bahar

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-kappa B/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 RXR alpha protein expression associated with a rise in the expression of TLR4, MyD88, phosphorylated TAK1, NF-kappa B p65, phosphorylated NF-kappa B p65, COX-2, and IL-1 beta proteins, in addition to COX-2 activity and levels of PGE(2) and IL-1 beta in the brains and spinal cords of the LPS-treated animals. Likely, decreased activity of TLR4/MyD88/TAK1/NF-kappa B/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.