title: Resveratrol Preconditioning Protects Against Cerebral Ischemic Injury via Nuclear Erythroid 2-Related Factor 2.
abstract: OBJECTIVE
  Nuclear erythroid 2 related factor 2 (Nrf2) is an astrocyte-enriched transcription factor that has previously been shown to upregulate cellular antioxidant systems in response to ischemia. Although resveratrol preconditioning (RPC) has emerged as a potential neuroprotective therapy, the involvement of Nrf2 in RPC-induced neuroprotection and mitochondrial reactive oxygen species production after cerebral ischemia remains unclear. The goal of our study was to study the contribution of Nrf2 to RPC and its effects on mitochondrial function.
  
  
  METHODS
  We used rodent astrocyte cultures and an in vivo stroke model with RPC. An Nrf2 DNA binding ELISA and protein analysis via Western blotting of downstream Nrf2 targets were performed to determine RPC-induced activation of Nrf2 in rat and mouse astrocytes. After RPC, mitochondrial function was determined by measuring reactive oxygen species production and mitochondrial respiration in both wild-type and Nrf2-/- mice. Infarct volume was measured to determine neuroprotection, whereas protein levels were measured by immunoblotting.
  
  
  RESULTS
  We report that Nrf2 is activated by RPC in rodent astrocyte cultures, and that loss of Nrf2 reduced RPC-mediated neuroprotection in a mouse model of focal cerebral ischemia. In addition, we observed that wild-type and Nrf2-/- cortical mitochondria exhibited increased uncoupling and reactive oxygen species production after RPC treatments. Finally, Nrf2-/- astrocytes exhibited decreased mitochondrial antioxidant expression and were unable to upregulate cellular antioxidants after RPC treatment.
  
  
  CONCLUSIONS
  Nrf2 contributes to RPC-induced neuroprotection through maintaining mitochondrial coupling and antioxidant protein expression.
authors.affiliation: From the Cerebral Vascular Disease Research Laboratories (S.V.N., K.R.D., I.S., M.A.P.-P.), Neuroscience Program (S.V.N., K.R.D., M.A.P.-P.), and Department of Neurology (S.V.N., K.R.D., I.S., M.A.P.-P.), University of Miami Miller School of Medicine, FL; and University of Miami Miller School of Medicine MD/PhD Program (S.V.N.).
authors.forename: Srinivasan V
authors.initials: SV
authors.lastname: Narayanan
authors.affiliation: From the Cerebral Vascular Disease Research Laboratories (S.V.N., K.R.D., I.S., M.A.P.-P.), Neuroscience Program (S.V.N., K.R.D., M.A.P.-P.), and Department of Neurology (S.V.N., K.R.D., I.S., M.A.P.-P.), University of Miami Miller School of Medicine, FL; and University of Miami Miller School of Medicine MD/PhD Program (S.V.N.).
authors.forename: Kunjan R
authors.initials: KR
authors.lastname: Dave
authors.affiliation: From the Cerebral Vascular Disease Research Laboratories (S.V.N., K.R.D., I.S., M.A.P.-P.), Neuroscience Program (S.V.N., K.R.D., M.A.P.-P.), and Department of Neurology (S.V.N., K.R.D., I.S., M.A.P.-P.), University of Miami Miller School of Medicine, FL; and University of Miami Miller School of Medicine MD/PhD Program (S.V.N.).
authors.forename: Isa
authors.initials: I
authors.lastname: Saul
authors.affiliation: From the Cerebral Vascular Disease Research Laboratories (S.V.N., K.R.D., I.S., M.A.P.-P.), Neuroscience Program (S.V.N., K.R.D., M.A.P.-P.), and Department of Neurology (S.V.N., K.R.D., I.S., M.A.P.-P.), University of Miami Miller School of Medicine, FL; and University of Miami Miller School of Medicine MD/PhD Program (S.V.N.). perezpinzon@miami.edu.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Perez-Pinzon
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; C495637:Nfe2l2 protein, rat; D017382:Reactive Oxygen Species; D013267:Stilbenes; D000077185:Resveratrol
keywords: ischemic preconditioning; mitochondria; reactive oxygen species; resveratrol