Abstract: Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist, exhibits significant neuroprotective effects in stroke and neurodegenerative diseases. However, the anti-inflammatory and barrier-protective effects of semaglutide and the mechanisms underlying its effects following traumatic brain injury remain unclear. In this study, we used mice to establish a model of controlled cortical impact injury to investigate the roles and effects of semaglutide on neuroinflammation, the integrity and permeability of the blood– brain barrier, brain edema, and the recovery of neurological function after traumatic brain injury. Our results showed that semaglutide treatment alleviated interleukin-17/NOD-like receptor pyrin domain-containing 3-induced neuroinflammation and upregulated the expression of tight junction proteins, thereby reducing brain leakage and edema while promoting the recovery of neurological function. Furthermore, transmission electron microscopy assessments demonstrated that semaglutide maintained the ultrastructure of the blood–brain barrier, strengthening the tight junctions between endothelial cell membranes. Mechanistically, semaglutide alleviated inflammatory conditions by interrupting the positive-feedback loop of inflammation in peripheral and innate immune cells induced by interleukin-17/NOD-like receptor pyrin domain-containing 3. Collectively, our findings reveal the dual anti-inflammatory and neuroprotective roles of semaglutide, providing important preclinical evidence for its clinical application in the acute phase of traumatic brain injury. 

Key words: apoptosis, blood–brain barrier, brain edema, glucagon-like peptide-1 receptor, interleukin-17, neuroinflammation, neuronal survival, secondary brain injury, semaglutide, traumatic brain injury