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.