The antioxidant effect of preischemic dexmedetomidine in a rat model: increased expression of Nrf2/HO-1 via the PKC pathway

Braz J Anesthesiol. 2023 Mar-Apr;73(2):177-185. doi: 10.1016/j.bjane.2021.08.005. Epub 2021 Sep 21.

Abstract

Background: The precise underlying mechanism of antioxidant effects of dexmedetomidine-induced neuroprotection against cerebral ischemia has not yet been fully elucidated. Activation of Nuclear factor erythroid 2-related factor (Nrf2) and Heme Oxygenase-1 (HO-1) represents a major antioxidant-defense mechanism. Therefore, we determined whether dexmedetomidine increases Nrf2/HO-1 expression after global transient cerebral ischemia and assessed the involvement of Protein Kinase C (PKC) in the dexmedetomidine-related antioxidant mechanism.

Methods: Thirty-eight rats were randomly assigned to five groups: sham (n...=...6), ischemic (n...=...8), chelerythrine (a PKC inhibitor; 5...mg.kg-1 IV administered 30...min before cerebral ischemia) (n...=...8), dexmedetomidine (100.....g.kg-1 IP administered 30...min before cerebral ischemia (n...=...8), and dexmedetomidine...+...chelerythrine (n...=...8). Global transient cerebral ischemia (10...min) was applied in all groups, except the sham group; histopathologic changes and levels of nuclear Nrf2 and cytoplasmic HO-1 were examined 24...hours after ischemia insult.

Results: We found fewer necrotic and apoptotic cells in the dexmedetomidine group relative to the ischemic group (p...<...0.01) and significantly higher Nrf2 and HO-1 levels in the dexmedetomidine group than in the ischemic group (p...<...0.01). Additionally, chelerythrine co-administration with dexmedetomidine attenuated the dexmedetomidine-induced increases in Nrf2 and HO-1 levels (p...<...0.05 and p...<...0.01, respectively) and diminished its beneficial neuroprotective effects.

Conclusion: Preischemic dexmedetomidine administration elicited neuroprotection against global transient cerebral ischemia in rats by increasing Nrf2/HO-1 expression partly via PKC signaling, suggesting that this is the antioxidant mechanism underlying dexmedetomidine-mediated neuroprotection.

Keywords: Antioxidant; Cerebral ischemia; Dexmedetomidine; Nuclear factor erythroid 2-related factor; Protein kinase C.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Antioxidants / pharmacology
  • Brain Ischemia*
  • Dexmedetomidine* / pharmacology
  • Heme Oxygenase-1 / metabolism
  • Heme Oxygenase-1 / pharmacology
  • Ischemic Attack, Transient*
  • NF-E2-Related Factor 2 / metabolism
  • NF-E2-Related Factor 2 / pharmacology
  • Neuroprotective Agents* / pharmacology
  • Oxidative Stress
  • Protein Kinase C / metabolism
  • Protein Kinase C / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury* / prevention & control

Substances

  • Heme Oxygenase-1
  • Antioxidants
  • Protein Kinase C
  • NF-E2-Related Factor 2
  • Dexmedetomidine
  • Neuroprotective Agents