Ticagrelor alleviates neuroinflammation after traumatic brain injury by inhibiting NLRP3 inflammasome-mediated pyroptosis.

Abstract

Traumatic brain injury (TBI) is often accompanied by secondary brain injury (SBI), with neuroinflammation being a core mechanism of SBI. Pyroptosis is a key driver of neuroinflammatory responses, and inhibiting pyroptosis can reduce neuroinflammation after TBI and promote tissue and functional recovery. The activation of the NLRP3 inflammasome mediates the classical pyroptosis pathway, and ticagrelor can inhibit NLRP3 inflammasome activation. This study aimed to investigate the differences in pyroptosis inhibition induced by TBI with different doses of ticagrelor by targeting the activation of the NLRP3 inflammasome. Mice were randomly divided into four groups: sham, TBI, 50 mg/kg ticagrelor treatment, and 150 mg/kg ticagrelor treatment. After 24 h of treatment, brain tissue surrounding the injury was collected for immunoblot detection of pyroptosis-related protein expression and ELISA detection of inflammatory cytokine release. On day 3 after treatment, BBB permeability and brain edema were assessed by injection of Evans blue and measurement of brain tissue water content. On day 7 after treatment, mice were sacrificed, and the extent of injury was assessed through hematoxylin and eosin and Nissl staining, while the levels of pyroptosis markers and neuroinflammation in brain tissue were detected by immunohistochemistry. On day 21 after treatment, the Morris water maze was used to evaluate neural function recovery. Compared with the TBI group, high-dose ticagrelor treatment inhibited pyroptosis in mouse brain tissue, reduced the release of inflammatory cytokines, alleviated brain edema, lowered neuroinflammation levels, and promoted neural function recovery (P < 0.05). Therefore, ticagrelor holds promise as a clinical drug for treating TBI.