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      A Small-Molecule-Inducible Nrf2-Mediated Antioxidant Response Provides Effective Prophylaxis against Cerebral Ischemia In Vivo

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          Abstract

          The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates expression of genes required for free radical scavenging, detoxification of xenobiotics, and maintenance of redox potential. Previously, activation of this pleiotropic response was neuroprotective in cell culture models that simulate components of stroke damage. However, the role of Nrf2 in limiting stroke damage in vivo remained unclear. We report that Nrf2 activation protects the brain from cerebral ischemia in vivo. Acute (1-3 d) intracerebroventricular or intraperitoneal pretreatment with tert-butylhydroquinone (tBHQ), an Nrf2 activity inducer, reduced cortical damage and sensorimotor deficit at 24 h and even 1 month after ischemia-reperfusion in rats. Cortical glutathione levels robustly increased with tBHQ administration to rats and Nrf2-expressing mice, but not Nrf2 -/- mice. Basal and inducible activities of antioxidant/detoxification enzymes in Nrf2 -/- mice were reduced when compared with Nrf2 +/+ controls. Interestingly, larger infarcts were observed in Nrf2 -/- mice at 7 d after stroke, but not at 24 h, suggesting that Nrf2 may play a role in shaping the penumbra well after the onset of ischemia. Neuronal death caused by a “penumbral” model of stroke, using intracortical endothelin-1 microinjection, was attenuated by tBHQ administration to Nrf2 +/+, but not to Nrf2 -/- mice, confirming the Nrf2-specific action of tBHQ in vivo. We conclude that Nrf2 plays a role in modulating ischemic injury in vivo. Accordingly, Nrf2 activation by small molecule inducers may be a practical preventative treatment for stroke-prone patients.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneuro
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          2 November 2005
          : 25
          : 44
          : 10321-10335
          Affiliations
          Departments of [1 ]Psychiatry and [2 ]Physiology, Kinsmen Laboratory of Neurological Research and Brain Research Center, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3
          Article
          PMC6725780 PMC6725780 6725780 002510321
          10.1523/JNEUROSCI.4014-05.2005
          6725780
          16267240
          9bef1203-cb5e-478c-8357-9dd7ce2ab45b
          Copyright © 2005 Society for Neuroscience 0270-6474/05/2510321-15.00/0
          History
          : 23 September 2005
          : 5 November 2004
          Categories
          Neurobiology of Disease
          Custom metadata
          10321
          ARTICLE
          true
          neurobiology-of-disease

          astrocyte,NF-E2-related factor,Nrf2,oxidative stress,NAD(P)H:quinone oxidoreductase,ischemia,brain,glutathione,antioxidant response element, tert-butylhydroquinone,endothelin-1,stroke,neuroprotection

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