Paclitaxel-induced peripheral neuropathy (PIPN) is one of the common adverse effects during the paclitaxel (PTX) treatment of cancer. In this study, we investigated the neuroprotective effects and mechanisms of thymoquinone (TQ) in the PIPN model. Through pain behavioral assays and histological assessment, we demonstrated that TQ significantly alleviated the nociceptive behavior, modulated the pathological changes in peripheral nerves, and decreased the expression of inflammatory factors TNF-α, IL-1β, and IL-6 induced by PIPN in mice. In addition, TQ significantly reversed the reduced viability and inflammatory response of primary DRG neurons caused by PTX. Moreover, the gene expression of related pathways was detected by Western blot, qPCR, and immunofluorescence, and the results showed that TQ exerts neuroprotective effects by regulating TLR4/MyD88 and its downstream NF-κB and MAPKs inflammatory pathways in vivo and in vitro. The treatment with TLR4 antagonist TAK-242 further indicated the important role of the TLR4/MyD88 signaling pathway in PIPN. Furthermore, molecular docking and a cellular thermal shift assay were used to confirm the interaction of TQ with TLR4. In summary, our study shows that TQ can inhibit inflammatory responses against PIPN by regulating TLR4 and MyD88 and its downstream inflammatory pathways.
Keywords: TLR4; inflammation; paclitaxel; pain; peripheral neuropathy; thymoquinone.