FIG. 8.

Pictorial description of MCC950 therapeutic effects on experimental TBI. In a simplified look, TBI instigates several deteriorating signals, that is, through ROS or damage-associated molecular pattern stimulation interfacing with the protective effectors like Akt phosphorylation. The damage signals are sensed by NLRP3 to recruit ASC to NRPL3 inflammasome assembly. TXNIP interacts with NLRP3 inflammasome to augment its cleavage activity on caspase-1 precursor leading to caspase-1 and subsequent IL-1β maturation. IL-1β may trigger a wide range of inflammatory reactions, which parallels NF-κB transcriptional activity and TNF-α overproduction. Apoptotic cell death involving caspase-3 and PARP follows the inflammatory propagation. According to our findings, MCC950 mitigates TBI-induced neuroinflammation and associated apoptotic cascades as determined by arrows with significant changes detected for the shaded ones. Such an ameliorating effect of MCC950 is mainly ascribed to specific inhibition of NLRP3 oligomerization and subsequent IL-1β maturation. Through a likely feedback mechanism, MCC950 may rescue Akt survival activity from deteriorating TBI outcomes. Akt, protein kinase B; pAkt, phosphorylated Akt; ASC, apoptosis-associated speck-like; DAMP, damage-associated molecular pattern; NF-κB, nuclear factor kappa B; NLRP3, nucleotide oligomerization domain (NOD)-like receptor protein-3; PARP, poly (ADP-ribose) polymerase; TBI, traumatic brain injury; ROS, reactive oxygen species; TXNIP, thioredoxin interacting protein; IL-1β, interleukin 1 beta; TNF-α, tumor necrosis factor alpha; p65, NF-κB/p65 subunit.