Garcinol Promotes Recovery After Spinal Cord Injury in Mouse by Modulating Microglial Polarization Through EGFR/PI3K/AKT Signaling

STUDY DESIGN: Preclinical experimental study. OBJECTIVE: To investigate the therapeutic potential of garcinol in spinal cord injury (SCI), focusing on its regulation of microglial polarization and underlying molecular mechanisms. SUMMARY OF BACKGROUND DATA: Secondary inflammation following SCI, primarily driven by overactivated microglia, exacerbates neurological deficits. Garcinol, a natural polyisoprenylated benzophenone, exhibits anti-inflammatory, antioxidant, and neuroprotective properties, but its efficacy in SCI has not been explored. MATERIALS AND METHODS: In vitro, BV2 microglial cells were stimulated with LPS to mimic the SCI inflammatory microenvironment and treated with garcinol to assess cytokine release, polarization, and proliferation. In vivo, T10-T11 contusive SCI was induced in mice, followed by garcinol administration. Functional recovery was evaluated using motor, bladder, and gait assessments. Network pharmacology, molecular docking, and transcriptomic analyses were performed to identify key targets and pathways, with mechanistic validation using EGFR/PI3K/AKT modulators. RESULTS: In vitro, garcinol promoted microglial polarization toward an anti-inflammatory phenotype by reducing proinflammatory cytokines (TNF-α, IL-6), suppressing M1 markers (iNOS, CD86), and enhancing M2 markers (Arg-1, CD163). Critically, in a mouse model of contusive SCI, daily garcinol administration (20 mg/kg, i.p., 28 d) significantly attenuated microglial activation and neuroinflammation, mitigated secondary tissue damage, which consequently promoted functional recovery, as evidenced by improved locomotor (BMS score) and bladder function. Network and mechanistic studies identified that these beneficial effects were mediated through the inhibition of the EGFR/PI3K/AKT pathway. Collectively, these findings underscore the translational potential of garcinol as a multitarget therapeutic candidate for SCI. CONCLUSION: Garcinol alleviates secondary inflammation and enhances neurological recovery after SCI by modulating microglial polarization through the EGFR/PI3K/AKT pathway. These findings provide a theoretical and experimental basis for developing garcinol as a multitarget therapeutic candidate for SCI.