Perioperative Medicine  |   March 2017
Kelch-like ECH-associated Protein 1-dependent Nuclear Factor-E2–related Factor 2 Activation in Relation to Antioxidation Induced by Sevoflurane Preconditioning
Author Notes
  • From the Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China (M.C., L.T., B.D., W.H., L.S., H.D.); and Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing, China (L.T.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • M.C. and L.T. contributed equally to this article.
    M.C. and L.T. contributed equally to this article.×
  • Submitted for publication March 17, 2016. Accepted for publication November 21, 2016.
    Submitted for publication March 17, 2016. Accepted for publication November 21, 2016.×
  • Address correspondence to Dr. Dong: Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China. hldong6@hotmail.com. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Basic Science
Perioperative Medicine   |   March 2017
Kelch-like ECH-associated Protein 1-dependent Nuclear Factor-E2–related Factor 2 Activation in Relation to Antioxidation Induced by Sevoflurane Preconditioning
Anesthesiology 3 2017, Vol.126, 507-521. doi:10.1097/ALN.0000000000001485
Anesthesiology 3 2017, Vol.126, 507-521. doi:10.1097/ALN.0000000000001485
Abstract

Background: The authors have reported that antioxidative effects play a crucial role in the volatile anesthetic-induced neuroprotection. Accumulated evidence shows that endogenous antioxidation could be up-regulated by nuclear factor-E2–related factor 2 through multiple pathways. However, whether nuclear factor-E2–related factor 2 activation is modulated by sevoflurane preconditioning and, if so, what is the signaling cascade underlying upstream of this activation are still unknown.

Methods: Sevoflurane preconditioning in mice was performed with sevoflurane (2.5%) 1 h per day for five consecutive days. Focal cerebral ischemia/reperfusion injury was induced by middle cerebral artery occlusion. Expression of nuclear factor-E2–related factor 2, kelch-like ECH-associated protein 1, manganese superoxide dismutase, thioredoxin-1, and nicotinamide adenine dinucleotide phosphate quinolone oxidoreductase-1 was detected (n = 6). The antioxidant activities and oxidative product expression were also examined. To determine the role of kelch-like ECH-associated protein 1 inhibition-dependent nuclear factor-E2–related factor 2 activation in sevoflurane preconditioning-induced neuroprotection, the kelch-like ECH–associated protein 1-nuclear factor-E2–related factor 2 signal was modulated by nuclear factor-E2–related factor 2 knockout, kelch-like ECH-associated protein 1 overexpression lentivirus, and kelch-like ECH-associated protein 1 deficiency small interfering RNA (n = 8). The infarct volume, neurologic scores, and cellular apoptosis were assessed.

Results: Sevoflurane preconditioning elicited neuroprotection and increased nuclear factor-E2–related factor 2 nuclear translocation, which in turn up-regulated endogenous antioxidation and reduced oxidative injury. Sevoflurane preconditioning reduced kelch-like ECH-associated protein 1 expression. Nuclear factor-E2–related factor 2 ablation abolished neuroprotection and reversed sevoflurane preconditioning by mediating the up-regulation of antioxidants. Kelch-like ECH-associated protein 1 overexpression reversed nuclear factor-E2–related factor 2 up-regulation and abolished the neuroprotection induced by sevoflurane preconditioning. Kelch-like ECH-associated protein 1 small interfering RNA administration improved nuclear factor-E2–related factor 2 expression and the outcome of mice subjected to ischemia/reperfusion injury.

Conclusions: Kelch-like ECH-associated protein 1 down-regulation–dependent nuclear factor-E2–related factor 2 activation underlies the ability of sevoflurane preconditioning to activate the endogenous antioxidant response, which elicits its neuroprotection.