Mechanisms by which cannabidiol promotes peripheral nerve regeneration

Cannabidiol, a cannabis-derived non-psychoactive compound, possesses neuroprotective potential; however, the specific mechanisms by which it promotes peripheral nerve repair remain unclear. This study aimed to elucidate the mechanisms underlying the neurorepair effects of cannabidiol, focusing on the regulation of nerve injury and repair through the "gut-nerve axis." We used a sciatic nerve crush model, combined with multi-omics analyses and molecular validation, to investigate and verify the mechanisms underlying cannabidiol mediated peripheral nerve injury repair both in vivo and in vitro. Following peripheral nerve injury, the abundance of the probiotic Akkermansia muciniphila was significantly reduced. cannabidiol treatment restored Akkermansia muciniphila abundance and was accompanied by increased levels of 3-hydroxyphenylacetic acid in both the serum and injured sciatic nerve. Oral administration of cannabidiol promoted PNI repair by improving the morphology of the injured nerve, increasing the static sciatic index in mice, and alleviating gastrocnemius muscle atrophy. Importantly, antibiotic-induced dysbiosis significantly attenuated the therapeutic efficacy of cannabidiol, whereas Akkermansia muciniphila supplementation restored these neuroregenerative effects. Mechanistically, transcriptomic sequencing indicated that 3-hydroxyphenylacetic acid effectively inhibited MAPK signaling activation in Schwann cells, thereby reducing the secretion of inflammatory factors and alleviating inflammation to create a favorable microenvironment for repair of peripheral nerve injury. Exogenous 3-hydroxyphenylacetic acid supplementation similarly promoted recovery of peripheral nerve injury. This study reveals, for the first time, a novel "cannabidiol-Akkermansia muciniphila-3-hydroxyphenylacetic acid-mitogen-activated protein kinase axis" that plays a pivotal role in peripheral nerve repair. These findings deepen our understanding of the neuroprotective mechanisms of cannabidiol and provide an important theoretical foundation for developing novel therapeutic strategies targeting the gut microbiome to promote repair of peripheral nerve injury.