Madecassoside Accelerates Nerve Regeneration by Promoting M2 Macrophage Polarization via TXNIP/NLRP3/GSDMD Pathway

The functional re-establishment and reinnervation of peripheral nerves following crush injuries represent the major clinical challenges for surgeons. Sustained existence of inflammatory microenvironment is detrimental for peripheral nerve regrowth following crush injuries, which results in the pathogenesis of pain over time. Here, we report that madecassoside (MA), a major active component generated from Centella asiatica, remarkably accelerates neuronal repair post-crush. In the present study, we find that motor functional exacerbation and gastrocnemius muscle atrophy are notably reversed in vivo through intragastric administration of MA. We also find that MA administration triggers macrophage migration for recruitment and M2 phenotype polarization, both of which play key roles in modulating inflammatory microenvironment within damaged nerves. However, this regulated capacity of MA on macrophage functions can be blunted through macrophage depletion in vivo. Mechanistically, MA inhibits TXNIP/NLRP3/GSDMD signaling pathway, resulting in inflammatory factors downregulation post-damage and regeneration improvement. Additionally, inhibiting this pathway recapitulates the effects of MA on promoting M2 macrophage transition and nerve regrowth. Our results identify MA as a favorable agent for sciatic nerve regeneration.