LDC7559 Exerts Neuroprotective Effects by Inhibiting GSDMD-Dependent Pyroptosis of Microglia in Mice with Traumatic Brain Injury
Pyroptosis is considered a critical factor in the recovery of neurological function following traumatic brain injury (TBI). Brain injury triggers a molecular signaling cascade associated with pyroptosis and inflammation, involving NLRP3, inflammatory cytokines, caspase-1, gasdermin D (GSDMD), and other pyroptosis-related proteins. In this study, we investigated the neuroprotective effects of LDC7559, a GSDMD inhibitor. Mice were administered LDC7559, siRNA-GSDMD (si-GSDMD), or an equivalent solvent, using both an in vitro lipopolysaccharide + nigericin (LPS + Nig) model and an in vivo controlled cortical impact brain injury model. The results indicated that treatment with LDC7559 or si-GSDMD decreased levels of inflammation and pyroptosis in both models. Immunofluorescence staining, brain water content measurement, hematoxylin and eosin staining, and behavioral assessments demonstrated that LDC7559 or si-GSDMD inhibited microglial proliferation, alleviated cerebral edema, reduced brain tissue loss, and promoted brain function recovery. These findings suggest that LDC7559 may inhibit pyroptosis and reduce inflammation by targeting GSDMD, thereby facilitating the recovery of neurological function.