Protective effects of combined treatment with mild hypothermia and edaravone against cerebral ischemia/reperfusion injury via oxidative stress and Nrf2 pathway regulation

Int J Oncol. 2020 Aug;57(2):500-508. doi: 10.3892/ijo.2020.5077. Epub 2020 Jun 4.

Abstract

Mild hypothermia (MH) and edaravone (EDA) exert neuroprotective effects against cerebral ischemia/reperfusion (I/R) injury through activation of the nuclear factor erythroid 2‑related factor 2 (Nrf2) pathway. However, whether MH and EDA exert synergistic effects against cerebral I/R injury remains unknown. The aim of the present study was to investigate the effects and mechanism of action of MH in combination with EDA in cerebral I/R injury. A rat cerebral I/R injury model was constructed by middle cerebral artery occlusion (MCAO) followed by reperfusion, and the mice were treated by MH, EDA or the inhibitor of the Nrf2 signaling pathway brusatol (Bru). It was observed that mice treated by MCAO had higher neurological deficit scores and oxidative stress levels, and low spatial learning and memory capacity; moreover, the CA1 region of the hippocampi of the mice exhibited reduced neuronal density and viability, and reduced mitochondrial dysfunction. However, MH in combination with EDA reversed the effects of MCAO, which were blocked by Bru injection. The levels of glutathione (GSH), GSH peroxidase, catalase and superoxide dismutase in rat ischemic hemisphere tissues were reduced by Bru. Western blotting demonstrated that the combined treatment with MH and EDA promoted the nuclear localization of Nrf2, and increased the levels of NAD(P)H quinone oxidoreductase and heme oxygenase (HO)‑1. In conclusion, MH combined with EDA exerted synergistic neuroprotective effects against cerebral I/R injury involving changes in the Nrf2/HO‑1 pathway.

Keywords: mild hypothermia; edaravone; cerebral ischemia/reperfusion injury; nuclear factor erythroid 2-related factor 2.

MeSH terms

  • Animals
  • Brain Ischemia / complications
  • Brain Ischemia / pathology
  • Brain Ischemia / therapy*
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / pathology
  • Combined Modality Therapy / methods
  • Disease Models, Animal
  • Edaravone / administration & dosage*
  • Humans
  • Hypothermia, Induced*
  • Male
  • NF-E2-Related Factor 2 / antagonists & inhibitors
  • NF-E2-Related Factor 2 / metabolism
  • Neuroprotective Agents / administration & dosage*
  • Oxidative Stress / drug effects
  • Quassins / administration & dosage
  • Rats
  • Reperfusion Injury / etiology
  • Reperfusion Injury / pathology
  • Reperfusion Injury / therapy*
  • Signal Transduction / drug effects

Substances

  • NF-E2-Related Factor 2
  • Neuroprotective Agents
  • Nfe2l2 protein, rat
  • Quassins
  • brusatol
  • Edaravone