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Nuclear Factor Erythroid 2-Related Factor 2 is Essential for Low-Normobaric Oxygen Treatment-Mediated Blood-Brain Barrier Protection Following Ischemic Stroke

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Abstract

Cerebral ischemia/reperfusion (I/R) injury increases blood-brain barrier (BBB) permeability, leading to hemorrhagic transformation and brain edema. Normobaric oxygen (NBO) is a routine clinical treatment strategy for this condition. However, its neuroprotective effects remain controversial. This study investigated the effect of different NBO concentrations on I/R injury and explores the involvement of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the underlying mechanism. A mouse middle cerebral artery occlusion (MCAO) model, and an oxygen and glucose deprivation (OGD) model featuring mouse brain microvascular endothelial cells (ECs) called bEnd.3, were used to investigate the effect of NBO on I/R injury. A reactive oxygen species (ROS) inducer and Nrf2-knockdown by RNA were used to explore whether the Nrf2 pathway mediates the effect of NBO on cerebrovascular ECs. In the early stage of MCAO, 40% O2 NBO exposure significantly improved blood perfusion in the ischemic area and effectively relieved BBB permeability, cerebral edema, cerebral injury, and neurological function after MCAO. In the OGD model, 40% O2 NBO exposure significantly reduced apoptosis, inhibited ROS generation, reduced ER stress, upregulated the expression of tight junction proteins, and stabilized the permeability of ECs. Blocking the Nrf2 pathway nullified the protective effect of 40% O2 NBO on ECs after OGD. Finally, our study confirmed that low concentrations of NBO have a neuroprotective effect on I/R by activating the Nrf2 pathway in ECs.

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Data Availability

All original data will be made available on reasonable request to Zhen-Hong Wang.

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Funding

This study was financially supported by the National Natural Science Foundation of China (82071290, 82201623), and the Natural Science Foundation of Shanghai Committee of Science and Technology Commission (no. 20ZR1433400).

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Authors and Affiliations

  1. Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Xiao-Xiao Ma, Hai-Yi Xie, Xiao-Jing Wang, Wei Zhou & Zhen-Hong Wang

  2. Central Laboratory, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Pin-Pin Hou

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Contributions

XM, YX and PH performed the experiments, XJ, WZ and HW generate the idea and design the experiments. XM, YX, PH, XJ, WZ collected the data and performed the analysis. XM and YX wrote the manuscript, WZ supervised the project and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Wei Zhou or Zhen-Hong Wang.

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The authors have no relevant financial or non-financial interests to disclose.

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All animal experiments were approved by the Renji Hospital Institutional Animal Care and Use Committee (NO. RJ-2017-10-10) and performed in accordance with the Institutional Guidelines for animals Care and Use.

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Ma, XX., Xie, HY., Hou, PP. et al. Nuclear Factor Erythroid 2-Related Factor 2 is Essential for Low-Normobaric Oxygen Treatment-Mediated Blood-Brain Barrier Protection Following Ischemic Stroke. Mol Neurobiol 61, 2938–2948 (2024). https://doi.org/10.1007/s12035-023-03767-0

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