Targeting PTGS2 Attenuates Neuroinflammation and Glial Scar Formation: The Neuroprotective Mechanism of Luteolin in Spinal Cord Injury

Objective Spinal cord injury (SCI) is a complex neurological disorder that frequently leads to paraplegia and has limited treatment options. Taohong Siwu Decoction (THSWD), a traditional Chinese medicine formula known for promoting blood circulation and removing blood stasis, has shown potential for facilitating spinal cord repair. This study sought to identify its active monomeric compound and elucidate the mechanism underlying its neuroprotective effects in SCI. Materials and Methods We screened THSWD's active components using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and identified their targets via the PubChem and UniProt databases. SCI-related genes were obtained from the GEO (dataset GSE151371), GeneCards, and Comparative Toxicogenomics (CTD) databases. A drug-disease-protein-protein interaction (PPI) network was constructed with Cytoscape to identify core compounds and targets, and molecular docking simulations assessed the binding affinity between the core monomer and its target. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses identified key pathways. The Basso Mouse Scale (BMS) and rotarod tests behaviorally evaluated the efficacy of the screened monomer, while immunohistochemistry and Western blotting explored its therapeutic mechanism in a mouse SCI model. Results From the six constituent herbs of THSWD, the TCMSP database identified 52 blood-brain barrier (BBB)-penetrating components and 210 potential targets. Integrating the GEO, GeneCards, and CTD databases yielded 213 SCI-related genes. PPI network analysis revealed core targets such as MMP9, PTGS2, and PPARG. KEGG pathway analysis showed significant enrichment in inflammation-related pathways, particularly the NF-κB signaling pathway (false discovery rate, FDR < 0.05). Drug-disease-PPI network analysis, using network centrality parameters (betweenness ≥ 1.67, closeness ≥ 0.39, degree ≥ 2) as criteria, identified luteolin as the core active monomer. Molecular docking confirmed that luteolin exhibited the strongest binding affinity for PTGS2 (binding energy: -8.9 kcal/mol). Luteolin administration significantly improved the motor function of SCI mice compared to the control group (P < 0.05). Immunofluorescence analysis demonstrated that luteolin suppressed glial cell activation, as shown by reduced GFAP expression. Western blot analysis further indicated that luteolin decreased the activation level of the NF-κB pathway (P < 0.05). Conclusion This study identifies luteolin as the active monomer in THSWD responsible for its therapeutic effects. The neuroprotective mechanism of luteolin involves targeting PTGS2, inhibiting the NF-κB inflammatory pathway, and suppressing GFAP-positive glial scar formation.