Role of reactive oxygen species in modulation of Nrf2 following ischemic reperfusion injury.
The transcriptional factor Nrf2 has a unique role in various physiological stress conditions, but its contribution to ischemia/reperfusion injury has not been fully explored. Therefore, wildtype (WT) and Nrf2 knockout (Nrf2(-/-)) mice were subjected to 90-min occlusion of the middle cerebral artery (MCA) followed by 24-h reperfusion to elucidate Nrf2 contribution in protecting against ischemia/reperfusion injury. Infarct volume, represented as percent of hemispheric volume, was significantly (P<0.05) larger in Nrf2(-/-) mice than in WT mice (30.8+/-6.1 vs. 17.0+/-5.1%). Furthermore, neurological deficit was significantly greater in the Nrf2(-/-) mice. To examine whether neuronal protection was mediated by Nrf2, neurons were treated with various compounds to induce excitotoxic or oxidative stress. Translocation of Nrf2 into the nucleus was increased by the free-radical donor tert-butylhydroperoxide, but not by glutamate or N-methyl-D-aspartic acid (NMDA). In addition, a common Nrf2 inducer, tert-butylhydroquinone, significantly attenuated neuronal cell death induced by tert-butylhydroperoxide (83.6+/-1.6 vs. 62.0+/-7.7%) but not as substantially when excitotoxicity was induced by NMDA (91.9+/-1.6 vs. 79.3+/-3.3%) or glutamate (87.8+/-1.5 vs. 80.2+/-2.6%). The results suggest that Nrf2 reduces ischemic brain injury by protecting against oxidative stress.
Shah
Z A
ZA
Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University, 720 Rutland Avenue, Ross 365, Baltimore, MD 21205, USA.
Li
R-C
RC
Thimmulappa
R K
RK
Kensler
T W
TW
Yamamoto
M
M
Biswal
S
S
Doré
S
S
D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*; D018709:Statistics, Nonparametric
D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species