Ursodeoxycholic Acid Confers Neuroprotection in Rats With Acute Cervical SCI and Attenuates NLRP3/Caspase‐1/GSDMD Pyroptotic Signaling

Spinal cord injury (SCI) leads to significant and enduring functional limitations for patients. Secondary injury is a pivotal determinant of functional recovery after SCI, with pyroptosis driven by the NLRP3 inflammasome and its downstream inflammatory cascade representing a crucial contributor to this process. Ursodeoxycholic acid (UDCA), an endogenous secondary bile acid, displays neuroprotective activity through antioxidant and anti-inflammatory actions and may suppress pyroptosis. This study aimed to explore the neuroprotective effects of UDCA against SCI and its underlying mechanisms. BV2 microglia were treated with LPS and UDCA, either individually or concurrently. Cell viability and NLRP3 inflammasome protein expression were evaluated by CCK-8 assay and immunofluorescence, respectively. Additionally, following establishment of a rat model of C5 cervical SCI, UDCA was administered by oral gavage for 7 days. Functional recovery, histopathological damage, key protein expression in the NLRP3/Caspase-1/GSDMD pyroptosis pathway, and downstream inflammation were analyzed using various techniques, including behavioral evaluation (Cylinder Rearing test), HE staining, Western blot, immunofluorescence, and ELISA. Results showed that appropriate concentrations of UDCA improved BV2 cell viability and inhibited LPS-stimulated NLRP3 upregulation. Oral gavage of UDCA was associated with better forelimb motor function and attenuated spinal histopathological injury in rats with acute C5 cervical SCI. Furthermore, this treatment correlated with altered abundance of key components within the SCI‑activated NLRP3/Caspase‑1/GSDMD pathway, lower Iba‑1 expression, and diminished serum concentrations of IL‑18, IL‑1β, and TNF‑α, suggestive of attenuated neural pyroptosis and dampening of excessive postinjury inflammation. Collectively, UDCA mitigates secondary injury and improves forelimb function in an acute C5 cervical SCI model, alongside attenuation of NLRP3/Caspase-1/GSDMD-mediated pyroptosis and subsequent inflammation. Targeting pyroptosis, UDCA holds promise as a novel therapeutic candidate for SCI.