title: Carbon monoxide-activated Nrf2 pathway leads to protection against permanent focal cerebral ischemia.
abstract: OBJECTIVE
  Carbon monoxide (CO) is a gaseous second messenger produced when heme oxygenase enzymes catabolize heme. We have demonstrated that CO can be therapeutic in ischemia-reperfusion brain injury; however, it is unclear whether CO can also offer protection in permanent ischemic stroke or what mechanism(s) underlies the effect. Heme oxygenase-1 neuroprotection was shown to be regulated by Nrf2; therefore, we investigated whether CO might partially exert neuroprotection by modulating the Nrf2 pathway.
  
  
  METHODS
  To evaluate the potential protective effects of CO, we exposed male wild-type and Nrf2-knockout mice to 250 ppm CO or control air for 18 hours immediately after permanent middle cerebral artery occlusion. Infarct volume and neurologic deficits were assessed on day 7. Molecular mechanisms of Nrf2 pathway activation by CO were also investigated.
  
  
  RESULTS
  Mice exposed to CO after permanent ischemia had 29.6±12.6% less brain damage than did controls at 7 days, although amelioration in neurologic deficits did not reach significance. Additionally, 18-hour CO treatment led to Nrf2 dissociation from Keap1, nuclear translocation, increased binding activity of Nrf2 to heme oxygenase-1 antioxidant response elements, and elevated heme oxygenase-1 expression 6 to 48 hours after CO exposure. The CO neuroprotection was completely abolished in Nrf2-knockout mice.
  
  
  CONCLUSIONS
  Low-concentration CO represent a neuroprotective agent for combination treatment of ischemic stroke, and its beneficial effect would be at least partially mediated by activation of the Nrf2 pathway.
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Dr, Biomed Sci J493, PO 100159, Gainesville, FL 32610, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Wangsen
authors.initials: W
authors.lastname: Cao
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
authors.forename: Sylvain
authors.initials: S
authors.lastname: Doré
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002248:Carbon Monoxide / Q000494:pharmacology*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020218:Response Elements / Q000235:genetics; D020521:Stroke / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000963:Antimetabolites; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1