Galangin Exerts Neuroprotective Effects in Spinal Cord Injury by Targeting the PI3K / AKT and JAK2 / STAT1 Pathways

Spinal cord injury (SCI) often leads to permanent neurological deficits, with no effective treatment currently available. Galangin is a naturally occurring flavonoid with anti-inflammatory and antiapoptotic activities; nevertheless, its efficacy, and molecular mechanisms in SCI remain unelucidated. First, network pharmacology and Gene Expression Omnibus database analyses were used to predict target molecules and galangin signaling pathways. In vitro, LPS-induced immortalized murine microglial (BV-2) and rat pheochromocytoma (PC12) cells co-cultured with conditioned medium were used to elucidate the mechanism via western blotting, immunofluorescence, qRT-PCR, ELISA, flow cytometry, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), surface plasmon resonance (SPR), and pathway agonist/inhibitor/siRNA rescue assays. In vivo, SCI rat models were established to validate the protective efficacy through behavioral, histological, and western blot analyses. Galangin alleviated pro-inflammatory polarization and neuroinflammation in BV-2 microglia through inhibiting the PI3K/AKT pathway. It also diminished neuronal apoptosis and enhanced axonal growth-associated markers expression in PC12 neurons by inhibiting the JAK2/STAT1 pathway. These mechanisms were further supported experimentally using pathway agonists, inhibitors, and gene knockdown. In rats, galangin improved motor function and reduced neuroinflammation and neuronal damage. In conclusion, galangin simultaneously inhibited both pathways to alleviate neuroinflammation, decrease neuronal damage, and upregulate axonal growth-associated markers, thereby improving neurological function in SCI. Thus, galangin is a potential protective candidate for SCI.