Ferulic acid alleviates sciatica by inhibiting neuroinflammation and promoting nerve repair via the TLR4/NF‐κB pathway

INTRODUCTION: Sciatica causes intense pain. No satisfactory therapeutic drugs exist to treat sciatica. This study aimed to probe the potential mechanism of ferulic acid in sciatica treatment. METHODS: Thirty‐two SD rats were randomly divided into 4 groups: sham operation, chronic constriction injury (CCI), mecobalamin, and ferulic acid. We conducted RNA sequencing, behavioral tests, ELISA, PCR, western blotting, and immunofluorescence analysis. TAK‐242 and JSH23 were administered to RSC96 and GMI‐R1 cells to explore whether ferulic acid can inhibit apoptosis and alleviate inflammation. RESULTS: RNA sequencing showed that TLR4/NF‐κB pathway is involved in the mechanism of sciatica. CCI induced cold and mechanical hyperalgesia; destroyed the sciatic nerve structure; increased IL‐1β, IL‐6, TNF‐α, IL‐8, and TGF‐β protein levels and IL‐1β, IL‐6, TNF‐α, TGF‐β, TLR4, and IBA‐1 mRNA levels; and decreased IL‐10 and INF‐γ protein levels and IL‐4 mRNA levels. Immunohistochemistry showed that IBA‐1, CD32, IL‐1β, iNOS, nNOS, COX2, and TLR4 expression was increased while S100β and Arg‐1 decreased. CCI increased TLR4, IBA‐1, IL‐1β, iNOS, Myd88, p‐NF‐κB, and p‐p38MAPK protein levels. Treatment with mecobalamin and ferulic acid reversed these trends. Lipopolysaccharide (LPS) induced RSC96 cell apoptosis by reducing Bcl‐2 and Bcl‐xl protein and mRNA levels and increasing Bax and Bad mRNA and IL‐1β, TLR4, Myd88, p‐NF‐κB, and p‐p38MAPK protein levels, while ferulic acid inhibited cell apoptosis by decreasing IL‐1β, TLR4, Myd88, p‐NF‐κB, and p‐p38MAPK levels and increasing Bcl‐2 and Bcl‐xl levels. In GMI‐R1 cells, Ferulic acid attenuated LPS‐induced M1 polarization by decreasing the M1 polarization markers IL‐1β, IL‐6, iNOS, and CD32 and increasing the M2 polarization markers CD206, IL‐4, IL‐10 and Arg‐1. After LPS treatment, IL‐1β, iNOS, TLR4, Myd88, p‐p38MAPK, and p‐NF‐κB levels were obviously increased, and Arg‐1 expression was reduced, while ferulic acid reversed these changes. CONCLUSION: Ferulic acid can promote injured sciatic nerve repair by reducing neuronal cell apoptosis and inflammatory infiltration though the TLR4/NF‐κB pathway.