Abstract

Background Brain endothelial cells (bECs) dysfunction plays a key role in blood-brain barrier (BBB) disruption after traumatic brain injury (TBI), contributing to a vicious cycle that worsens disease progression. Although neutrophil extracellular traps (NETs) are known to impair the BBB, their mechanisms in TBI remain unclear. Sivelestat sodium, an inhibitor of neutrophil elastase (NE) required for NETs formation, may offer a therapeutic strategy for TBI. Methods A controlled cortical impact (CCI) model was used to induce TBI in mice. NETs involvement was confirmed by immunofluorescence and Western blot, and the effect of sivelestat sodium on NETs formation in the peri-injury region was assessed. Transcriptome sequencing explored molecular mechanisms post-treatment. BBB integrity and vascular endothelial pyroptosis were evaluated via Western blot, immunofluorescence, and Evans blue extravasation. Results NETs expression in the peri-injury area peaked at 72 h after TBI and was reduced by sivelestat sodium treatment, which also improved neurological function in behavioral tests. Transcriptome sequencing unveiled sivelestat sodium may contribute to post-TBI recovery via neuroinflammatory and pyroptosis pathways. Furthermore, Western blot and immunofluorescence analyses demonstrated that sivelestat sodium treatment in TBI mice resulted in decreased expression of GSDMD-N and cleaved caspase-1 proteins, increased expression of tight junction proteins such as ZO-1, and reduced Evans blue extravasation. Conclusions This study suggests that sivelestat sodium protects the BBB and mitigates TBI-related injury by suppressing NETs formation and subsequent vascular endothelial pyroptosis, highlighting its therapeutic potential.