Rapamycin improves the neuroprotection effect of inhibition of NLRP3 inflammasome activation after TBI.

Inflammation is the focus of many studies on traumatic brain injury (TBI) treatment and outcomes improvement. Some studies have demonstrated that the inhibition of NOD-like receptor protein-3 (NLRP3) inflammasome activation is a potential strategy for TBI therapy. Mitophagy is thought to play a crucial role in pathological conditions of TBI. We hypothesize simultaneous mitophagy activation and NLRP3 inflammsome inhibition, plays preferable role in delaying the progression and nerve damage post-TBI. In this study, TBI-mice and oxygen and glucose deprivation (OGD)-induced primary cortical neurons were treated with MCC950 (a NLRP3 selective inhibitor) or Rapamycin (Rap, a mTOR inhibitor, stimulated autophagy and mitophagy). We evaluated the effects of Rap and NLRP3 inhibition on the neurological deficits, neurological damage, and inflammatory response, to determine if Rap further induced the neuroprotection of suppression of NLRP3 inflammasome activation in vivo and in vitro TBI-model. TBI induced NLRP3 inflammasome activation and mitochondrial dysfunction, including increased caspase-1 p20 expression, exacerbated the secretion of LDH, IL-1β and IL-18, and disorder of ATP, MMP, ROS and mitophagy (Pink1 and LC3 expression in mitochondria). NLRP3 inhibition and Rap attenuated the neurological damage and mitochondrial dysfunction, while combined treatment showed better neuroprotection compared with single treatment. Collectively, the data demonstrate that mitophagy and NLRP3 inflammasome have the interactivity, and Rap-induced mitophagy further enhances the neuroprotection of inhibition of NLRP3 inflammasome activation post-TBI. Our findings suggest that Rap-activated mitophagy combined with MCC950-induced NLRP3 inflammasome repression may be a potential strategy for TBI therapy.