Nuclear factor erythroid 2-related factor 2 is Essential for Low-Normobaric Oxygen Treatment Afforded Blood-Brain Barrier Protection Following Ischemic Stroke

Abstract Cerebral ischemia/reperfusion(I/R) injury increases blood-brain barrier (BBB) permeability, leading to hemorrhagic transformation and brain edema. Normobaric hyperoxia (NBO) is a routine clinical treatment strategy for this condition. However, its neuroprotective effects remain controversial. This study investigates 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 of mouse brain microvascular endothelial cells (bEnd.3), were used to investigate the effect of NBO on I/R injury. Reactive oxygen species (ROS) inducer and Nrf2 siRNA were used to explore the mechanisms of Nrf2 pathway in the effect of NBO on cerebrovascular endothelial cells. 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 of endothelial cells, 40% O2 NBO exposure significantly reduced cell apoptosis, inhibited ROS burst, reduced ER stress, upregulated the expression of tight junction proteins, and stabilized the permeability of endothelial cells. Blocking the Nrf2 pathway nullified the protective effect of 40% O2 NBO on endothelial cells after OGDNrf2. Finally, our study confirmed the low concentrations of NBO have a neuroprotective effect on I/R by activating the Nrf2 pathway in endothelial cells.