traumatic brain injury-induced downregulation of nrf2 activates inflammatory response and apoptotic cell death

Recent studies from our group and others have demonstrated that oxidative stress, ca2+ signaling, and neuroinflammation are major mechanisms contributing to post-traumatic neurodegeneration. the present study investigated the mechanisms of regulation of nuclear factor e2-related factor 2 (nrf2) and its role in regulating antioxidant genes and oxidative stress-induced neuroinflammation and neurodegeneration following tbi. nrf2 transcriptional system is the major regulator of endogenous defense mechanisms operating within the cells. wild-type (nrf2+/+) and nrf2-deficient mice (nrf2−/−) were subjected to 15 psi fluid percussion injury and demonstrated the regulatory role of nrf2 in the expression antioxidant genes and oxidative stress, neuroinflammation, and cell death. immunohistochemistry, q-rt-pcr, and western blotting techniques detected downregulation of nrf2 and antioxidant proteins such as ho-1, gpx1, gstm1, and nqo1 in mouse brain samples. further, our study demonstrated that the downregulation of nrf2 and antioxidant genes in tbi correlated with the induction of free radical-generating enzyme nadph oxidase 1 and inducible nitric oxide synthase and their corresponding oxidative/nitrosative stress markers 4-hydroxynonenal and 3-nitrotyrosine. the decrease in nrf2 with subsequent increase in oxidative stress markers led to the activation of mmp3/9, tgf-β1, and nf-kb that further led to neuroinflammation and apoptosis. the absence of nrf2 function in mice resulted in exacerbated brain injury as shown by the increased oxidative stress markers, pro-inflammatory cytokines, and apoptosis markers at 24 h after tbi. in conclusion, this study could establish the significance of nrf2 in transforming into a novel preventive approach against the pathophysiology of tbi. • traumatic brain injury impairs nrf2 signaling in mouse. • nrf2-mediated activation of antioxidant genes are altered after tbi. • impairment of nrf2 signaling leads to oxidative stress. • tbi-induced downregulation of nrf2 activates mmps, tgf-β1, and nf-kb. • nrf2 regulates neuroinflammation and apoptotic cell death in tb.