Bexarotene Ameliorates LPS-Induced Hyperalgesia: Contribution of TLR4/MyD88-Dependent Pro-Inflammatory, Anti-Apoptotic and Anti-Inflammatory Signaling Pathways

Background and Objective: One of the clinically approved retinoid X receptor (RXR) ligands, bexarotene, has been demonstrated to exert analgesic and anti-inflammatory effects in the experimental models of many inflammatory neurological diseases. The previous studies showed that bexarotene ameliorates the lipopolysaccharide (LPS)-induced hyperalgesia by increasing RXR expression associated with suppressed toll-like receptor (TLR)/myeloid differentiation factor (MyD) 88/transforming growth factor beta-activated kinase 1/nuclear factor-kappa B/cyclooxygenase-2 signaling pathway activity in the central nervous system (CNS). This study tested the hypothesis that the TLR/MyD88-dependent pro-inflammatory and anti-apoptotic signaling pathways mediate the ameliorating effect of bexarotene against LPS-induced inflammatory hyperalgesia. Materials and Methods: Brain and spinal cord tissues of bexarotene-treated mice were used for the measurement of tumor necrosis factor receptor-associated factor (TRAF) 6, inhibitor of IkB kinase (IKK) alpha, IKK beta, IKK gamma, inhibitor of kappa B (IkB)-alpha, mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase (ERK) 1/2, c-Jun, phosphoinositide 3-kinase (PI3K) p85 alpha, Akt1, cyclic adenosine monophosphate-response element-binding protein (CREB), B-cell lymphoma (Bcl)-2, peroxisome proliferator-activated receptor (PPAR) alpha, PPAR beta and PPAR gamma expression and/or activity by using the immunoblotting method. Results: Results showed that diminished protein expression and/or activity of PI3K p85 alpha, Akt1, CREB1, Bcl-2 and PPAR alpha/beta/gamma was associated with enhanced TRAF6, IKK alpha/beta/gamma, IkB-alpha, MEK1/2, ERK1/2 and c-jun proteins in the tissues of endotoxemic mice. These changes were ameliorated following bexarotene treatment. Conclusion: Thus, decreased activity of pro-inflammatory TLR4/MyD88-dependent TRAF6/IKK alpha/beta/gamma/I kappa B-gamma and TRAF6/MEK1/2/ERK1/2/AP-1 signaling pathways associated with an increase in the anti-apoptotic PI3K p85 alpha/Akt1/CREB1/Bcl-2 signaling pathway activity and anti-inflammatory PPAR alpha/beta/gamma proteins in the CNS contributes to the ameliorating effect of bexarotene against LPS-induced inflammatory hyperalgesia in mice.