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

Yu,Hang; Wu,Zhidian; Wang,Xiaozhi; Gao,Chang; Liu,Run; Kang,Fuxin; Dai,Mingming

doi:10.3892/ijo.2020.5077

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

Authors:
- Hang Yu
- Zhidian Wu
- Xiaozhi Wang
- Chang Gao
- Run Liu
- Fuxin Kang
- Mingming Dai
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Affiliations: Department of Critical Care Medicine, Hainan Medical University, Haikou, Hainan 570311, P.R. China, Department of Critical Care Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, P.R. China, Department of Pathophysiology, Hainan Medical University, Haikou, Hainan 570311, P.R. China, Department of Neurology, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, P.R. China
Published online on: June 4, 2020 https://doi.org/10.3892/ijo.2020.5077
Pages: 500-508
Copyright: © Yu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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