Galanin regulates M1/M2 polarization of microglia after spinal cord injury through TRPV1/Ca2+/CaMKII/NRF2 signaling pathway.

Medicine strategies focused on reducing secondary injury and delaying spinal cord injury (SCI) progression by targeting M1 microglial polarization remain uncommon. Galanin (GAL), a neuroendocrine peptide, is encoded by the GAL gene. In this study, we demonstrated that administration of recombinant human GAL peptides in a mouse model of SCI significantly elevated transient receptor potential vanilloid type 1 (TRPV1) receptor expression at the injury site through GALR2, substantially alleviating inflammation during the early stages post-injury. Nuclear factor erythroid 2-related factor 2 (NRF2) is a nuclear transcription factor responsible for activating genes that protect against oxidative stress and toxicity, thereby preserving redox equilibrium. Our results indicated that GAL modulates the Ca2+/CaMKII/NRF2 signaling pathway through TRPV1, thereby suppressing the polarization of microglia towards the pro-inflammatory M1 phenotype. This modulation contributes to an improved spinal cord microenvironment and exerts neuroprotective effects following SCI. These findings underscore the therapeutic potential of GAL as an early intervention for inflammation associated with SCI.