| First Author | Bhowmick S | Year | 2019 |
| Journal | J Mol Med (Berl) | Volume | 97 |
| Issue | 12 | Pages | 1627-1641 |
| PubMed ID | 31758217 | Mgi Jnum | J:293318 |
| Mgi Id | MGI:6452520 | Doi | 10.1007/s00109-019-01851-4 |
| Citation | Bhowmick S, et al. (2019) Traumatic brain injury-induced downregulation of Nrf2 activates inflammatory response and apoptotic cell death. J Mol Med (Berl) 97(12):1627-1641 |
| abstractText | Recent studies from our group and others have demonstrated that oxidative stress, Ca(2+) 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-beta1, 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. KEY MESSAGES: * 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-beta1, and NF-kB. * Nrf2 regulates neuroinflammation and apoptotic cell death in TB. |
