Abstract 12848: Edaravone Dexborneol Protects Against Cerebral Ischemia/Reperfusion -Induced Blood-Brain Barrier Dysfunction by Inhibiting Ferroptosis via Activation of Nrf-2/HO-1/GPX4 Signaling

Abstract

Background and aims: The blood-brain barrier (BBB) is a pivotal factor in the pathogenesis of cerebral ischemia-reperfusion (I/R) injury. Edaravone dexborneol (Eda.B) is a novel cytoprotective drug widely employed in ischemic stroke (IS). Recent research implicated ferroptosis in BBB disruption during cerebral ischemia. This study aimed to investigate the protective effects of Eda.B on the BBB in I/R from the standpoint of ferroptosis, exploring potential mechanisms and targets. Methods: An I/R model in Sprague-Dawley rats was established, and we assessed the effects of Eda.B by evaluating infarct volume, cellular apoptosis, and neurofunctional recovery through TTCstaining, TUNEL staining, and modified Garcia scoring system, respectively. The protective effects of Eda.B on BBB integrity was evaluated via Evans blue leakage measurement and protein expression of both ZO-1 and occludin. Additionally, we explored the correlation between ferroptosis and BBB integrity. Western blot analysis and immunohistochemical detection were used to detect changes in the expression levels of related proteins.Meanwhile the information of microscopic structural changes observation, GSH and MDA level measurements, and Fe 2+ tissue content determination were recorded. Bioinformatics analysis was also performed to probe the mechanisms of ferroptosis in BBB injury induced by cerebral ischemia, and we detected the expression of related proteins in the Nrf-2/HO-1 signaling pathway through western blot analysis. Results: Our findings revealed that Eda.B treatment enhanced neuro scores, diminished infarct volumes and cellular apoptosis, while ameliorated BBB integrity. Furthermore, expression of ZO-1, occludin, GPX4, and xCT protein expression was up-regulated, while 4-HNE expression was reduced in the Eda.B group. Eda.B also led to decreased MDA and Fe 2+ levels in the ipsilateral brain tissues, while GSH content was increased. Ultimately, an elevated expression of proteins associated with the Nrf-2/HO-1 signaling pathway has been discovered. Conclusions: Our study indicated that Eda.B safeguarded the blood-brain barrier (BBB) from cerebral I/R injury by inhibiting ferroptosis through the activation of the Nrf-2/HO-1/Gpx4 signaling pathway.