Urolithin B promotes the functional recovery of spinal cord injury by alleviating neuroinflammation via the inhibition of NLRP3 signaling pathway.

Background: Spinal cord injury (SCI) leads to motor, sensory and autonomic dysfunction with no effective therapy till now. The malignant microenvironment and glial scars at the injury site impede neural circuit remodeling and functional recovery of SCI. Urolithin B (UB), an intestinal metabolite of ellagitannin, possesses anti-inflammatory, antioxidant, antitumor and neuropharmacological activities.

Purpose: To investigate the effects and mechanism of UB in SCI recovery both in vitro and in vivo.

Methods: At the cellular level, the study focused on the effects of UB on H₂O₂-induced PC12 cells damage and LPS-induced HMC3 cells polarization. At the in vivo level, the repair effect of UB gavage on SCI mice was performed by behavioral analysis, immunofluorescence, histopathology, and ELISA. Finally, network pharmacology, transcriptome sequencing, molecular docking, DARTS, and reverse validation were conducted to explore the molecular mechanism by which UB promotes SCI repair.

Results: UB protected PC12 cells against H₂O₂-induced injury and decreased LPS-induced M1-type polarization of HMC3 cells. In addition, UB promoted nerve regeneration, regulated M1/M2 polarization of microglia, and reduced the formation of glial scars, thereby facilitating the motor function recovery of SCI mice. Further studies indicated that UB inhibited the NLRP3/Caspase-1/IL-1β pathway both in vivo and in vitro to reduce neuroinflammation. In contrast, BMS-986,299 (an agonist of NLRP3 inflammasome) attenuated the restorative effects of UB in SCI mice.

Conclusion: UB inhibits the NLRP3/Caspase-1/IL-1β signaling pathway and M1 polarization of microglia to attenuate neuroinflammation and promote the functional recovery of SCI mice. Therefore, UB may be a potential therapeutic agent for the treatment of SCI.