Inhibition of NOX2-NLRP1 signaling pathway protects against chronic glucocorticoids exposure-induced hippocampal neuronal damage.

Glucocorticoids (GCs) exposure has deleterious alteration on the structure and function in hippocampal neurons. NADPH oxidase 2 (NOX2) is a major contributor to oxidative stress in neurological diseases, and NLRP1 inflammasome can be activated in response to oxidative stress. We hypothesize that inhibition of NOX2-mediated NLRP1 inflammasome activation may protect against chronic GCs exposure-induced neuronal injury. In this study, the lentivirus with NLRP1-siRNA was injected into the hippocampus of male mice which were then treated with dexamethasone (DEX, 5 mg/kg) for 28 d. The data indicated that NLRP1-siRNA treatment down-regulated the NLRP1 expression and significantly improved the exploratory behavior and spatial memory deficits in open field tests and Morris water maze which were deteriorated by chronic DEX treatment in mice. Additionally, inhibition of NLRP1 expression significantly alleviated neuronal degeneration and increased MAP2 expression in the hippocampus in mice. Meanwhile, the results showed that DEX exposure increased NOX2, p22phox and p47phox expression in hippocampus tissue in mice. We further examined the effect of tempol (ROS scavenger) and apocynin (NOX inhibitor) treatment on NLRP1 inflammasome activation in chronic DEX-treated hippocampal neurons. The results revealed that the tempol (50 μM) and apocynin (50 μM) treatment significantly decreased generation of ROS, expression of NOX2 and NLRP1-related protein in DEX-treated hippocampal neurons. These data indicate that NOX2-mediated NLRP1 activation involves in chronic GCs exposure-induced neuronal injury and inhibition of NOX2-NLRP1 signaling pathway protects against GCs-induced neuronal damage.