Metformin induces M2 polarization via AMPK/PGC-1a/PPAR-? pathway to improve peripheral nerve regeneration

Objectives: Investigating the effect of metformin on peripheral nerve regeneration and the molecular mechanism. Methods: In this study, a rat model of sciatic nerve injury and an inflammatory bone marrow-derived macrophage (BMDM) cell model were established. We assessed the sensory and motor function of the hind limbs four weeks after sciatic nerve injury, immunofluorescence was used to detect axonal regeneration and myelin formation, as well as local macrophage subtypes. We investigated the polarizing effect of metformin on inflammatory macrophages, and western blotting was applied to detect the molecular mechanisms behind it. Results: Metformin treatment accelerated functional recovery, axon regeneration and remyelination, and promoted M2 macrophage polarization. In vivo, metformin transformed pro-inflammatory macrophages into pro-regeneration M2 macrophages. Protein expression levels of phosphorylated AMP-activated protein kinase (p-AMPK), proliferator-activated receptor-? co-activator 1a (PGC-1a), and peroxisome proliferator-activated receptor-? (PPAR-?) increased upon metformin treatment. Moreover, inhibition of AMPK abolished the effects of metformin treatment on M2 polarization. Conclusion: Metformin promoted M2 macrophage polarization by activating the AMPK/PGC-1a/PPAR-? signaling axis, thereby promoting peripheral nerve regeneration.