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

• Published in: CNS neuroscience & therapeutics Vol. 29; no. 4; pp. 1000 - 1011
• Main Authors: Zhang, Di, Jing, Bei, Chen, Zhen‐ni, Li, Xin, Shi, Hui‐mei, Zheng, Ya‐chun, Chang, Shi‐quan, Gao, Li, Zhao, Guo‐ping
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.04.2023; John Wiley and Sons Inc
• Subjects: Acids; Animals; Anti-inflammatory agents; Antibodies; Apoptosis; BAX protein; Bcl-2 protein; Bcl-x protein; Biotechnology; CCI; Coumaric Acids - pharmacology; Coumaric Acids - therapeutic use; Cyclooxygenase-2; Enzyme-linked immunosorbent assay; Ferulic acid; GMI‐R1; Hyperalgesia; Immunofluorescence; Immunohistochemistry; Inflammation; Interleukin 10; Interleukin 4; Interleukin 6; Interleukin 8; Interleukin-10 - metabolism; Interleukin-4 - metabolism; Interleukin-6 - metabolism; Kinases; Lipopolysaccharides; Lipopolysaccharides - toxicity; mRNA; MyD88 protein; Myeloid Differentiation Factor 88 - metabolism; Neuroinflammatory Diseases - drug therapy; Neuroinflammatory Diseases - metabolism; NF-kappa B - metabolism; NF-κB protein; NF‐κB; Nitric-oxide synthase; Nonsteroidal anti-inflammatory drugs; Original; Pain; Pain perception; Polarization; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; RSC96; Sciatic nerve; sciatica; Sciatica - drug therapy; Sciatica - metabolism; Signal Transduction; TLR4; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Tumor Necrosis Factor-alpha - metabolism; Western blotting; Beijing China; China; NF-κB; sciatica; ferulic acid; pain; RSC96; inflammation; CCI; TLR4; GMI-R1
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.14060

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. Ferulic acid promotes sciatic nerve repair by inhibiting Schwann cell apoptosis and promoted the transformation of M1 GMI‐R1 microglia to M2 microglia to relieve inflammatory infiltration though the TLR4/NF‐κB pathway.