Carbon monoxide-activated Nrf2 pathway leads to protection against permanent focal cerebral ischemia

Bing Wang, Wangsen Cao, Shyam Biswal, Sylvain Doré

Research output: Contribution to journalArticle

Abstract

Background and Purpose-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.

Original languageEnglish (US)
Pages (from-to)2605-2610
Number of pages6
JournalStroke
Volume42
Issue number9
DOIs
StatePublished - Sep 2011

Fingerprint

Carbon Monoxide
Brain Ischemia
Heme Oxygenase-1
Neurologic Manifestations
Knockout Mice
Stroke
Antioxidant Response Elements
Heme Oxygenase (Decyclizing)
Middle Cerebral Artery Infarction
Second Messenger Systems
Neuroprotective Agents
Reperfusion Injury
Heme
Brain Injuries
Ischemia
Air

Keywords

  • carboxyhemoglobin
  • heme oxygenase
  • mouse
  • neuroprotection
  • stroke

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialized Nursing

Cite this

Carbon monoxide-activated Nrf2 pathway leads to protection against permanent focal cerebral ischemia. / Wang, Bing; Cao, Wangsen; Biswal, Shyam; Doré, Sylvain.

In: Stroke, Vol. 42, No. 9, 09.2011, p. 2605-2610.

Research output: Contribution to journalArticle

Wang, Bing ; Cao, Wangsen ; Biswal, Shyam ; Doré, Sylvain. / Carbon monoxide-activated Nrf2 pathway leads to protection against permanent focal cerebral ischemia. In: Stroke. 2011 ; Vol. 42, No. 9. pp. 2605-2610.
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