Metformin induced M2 polarization to improve peripheral nerve regeneration by regulating AMPK/PGC-1α/PPAR-γ pathway

Abstract Peripheral nerve regeneration is a complex process that involves many signaling pathways, and M2 macrophage polarization was recognized to play a pivotal role in this process. The neuroprotective effects of metformin have attracted wide attention, but few reports focusedon the potentialeffects of metforminin immunomodulatory properties to improve the peripheral nerve regeneration by affecting M2 macrophage polarization. In this study, a rat model of sciatic nerve injury and an inflammatory model of bone marrow-derived macrophage (BMDM) cells were established to examine the potential mechanism of metformin treatment in peripheral nerve repair. Our research demonstrated that metformin treatment was able to accelerate functional recovery, axon regeneration and remyelination, and promote M2 macrophage polarization. In vivo, metformin could transform pro-inflammation macrophages into pro-regeneration M2 macrophages. It was also found that the levels of relative proteins of p-AMPK, PGC-1α, and PPAR-γ were significantly increased after metformin treatment. Moreover, the blockage of AMPK abolished the effects of metformin treatment on M2 polarization. Our data indicated that metformin promoted the macrophage polarization towards M2 phenotype by activating the AMPK/PGC-1α/PPAR-γ signaling axis so as to promote peripheral nerve regeneration. These findings may contribute to a more comprehensive understanding on the molecular mechanism of metformin treatment and its potential in peripheral nerve regeneration.