The Dual Role of Gastrodin in Spinal Cord Injury: Microglial Phenotype Switching and Neuronal Survival via <scp>PI3K</scp> / <scp>AKT</scp> Activation

BACKGROUND: Spinal cord injury (SCI) triggers a complex secondary cascade, the defining feature of which is neuroinflammation. This amplifies tissue damage and impedes neurological recovery. Microglial polarization is a critical event in this process, yet effective modulation strategies remain limited. OBJECTIVE: This study aimed to investigate whether gastrodin (GAS), a natural phenolic glycoside, could provide neuroprotection and promote functional recovery following SCI by modulating microglial polarization and to elucidate the underlying molecular mechanism. METHODS: We employed a combination of behavioral, histological, and molecular assays, and a microglia-neuron co-culture system under inflammatory conditions, using a rat contusion SCI model and LPS-stimulated BV2 microglia in vitro. The role of the PI3K/AKT signaling pathway was specifically investigated using the inhibitor LY294002. RESULTS: The administration of GAS markedly enhanced locomotor function, diminished lesion volume, and promoted neuronal survival in a dose-dependent manner in vivo. GAS mitigated the inflammatory response by reducing M1 markers (iNOS and CD86) and augmenting M2 markers (Arg1 and CD206) within the injured spinal cord and BV2 microglia. Additionally, GAS exhibited a direct anti-apoptotic effect on neurons in co-culture. Mechanistically, GAS significantly activated the PI3K/AKT signaling pathway. Notably, the PI3K inhibitor LY294002 completely nullified the anti-inflammatory and anti-apoptotic effects of GAS, underscoring the central role of this pathway in mediating GAS's effects. CONCLUSION: This study demonstrates that GAS confers multifaceted protection against SCI by modulating microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype and by directly inhibiting neuronal apoptosis, primarily through activation of the PI3K/AKT signaling pathway. These findings indicate that GAS holds significant potential as a therapeutic candidate for the treatment of SCI.