The role of Nrf2 signaling in the regulation of antioxidants and detoxifying enzymes after traumatic brain injury in rats and mice.
OBJECTIVE
To determine whether Nrf2 signaling pathway activation could attenuate oxidative stress and neuronal damage following traumatic brain injury (TBI).


METHODS
Controlled cortical impact (CCI) injury was performed in Sprague-Dawley rats and Nrf2-knockout or control mice. Sulforaphane (SFN), a potent Nrf2 activator, was used to activate Nrf2. Oxidative stress, lesion volume, neuron degeneration, and neurologic dysfunction were determined using biochemical, histopathological and neuroethologic approaches. Protein and mRNA levels of Nrf2 and the antioxidant enzymes heme oxygenase 1 (HO-1) and NAD(P)H:quinine oxidoreductase 1 (NQO1) were assessed using Western blot analysis and RT-PCR.


RESULTS
Activation of Nrf2 by SFN( 5 mg/kg, ip) induced the nuclear translocation and activation of Nrf2, which resulted in an up-regulation of Nrf2-dependent antioxidant enzymes and a reduction of oxidative damage after TBI. In accordance with these biochemical changes, SFN also significantly reduced neuronal death, contusion volume, and neurological dysfunction after TBI. Furthermore, Nrf2-knockout mice showed more severe oxidative stress and neurologic deficits after TBI and did not benefit from the effects of SFN.


CONCLUSIONS
Nrf2 plays a pivotal role in cell defenses against the oxidative stress of TBI. In addition, pharmacological activation of the Nrf2 signaling pathway by small molecule inducers such as SFN attenuated oxidative stress and neuronal damage following TBI.
Department of Neurosurgery, 2nd Affiliated Hospital, Zhejiang University, Hangzhou, China.
Yuan
Y
Hong
Wei
W
Yan
Sheng
S
Chen
Chong-ran
CR
Sun
Jian-min
JM
Zhang
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D051547:Heme Oxygenase-1 / Q000378:metabolism; D017879:Isothiocyanates; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology / Q000627:therapeutic use
D000975:Antioxidants; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D013454:Sulfoxides; D013861:Thiocyanates; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C016766:sulforaphane