NRF2 activation ameliorates blood–brain barrier injury after cerebral ischemic stroke by regulating ferroptosis and inflammation

• Published in: Scientific reports Vol. 14; no. 1; p. 5300
• Main Authors: Fan, Wei, Chen, Hongping, Li, Meng, Fan, Xuehui, Jiang, Fangchao, Xu, Chen, Wang, Yingju, Wei, Wan, Song, Jihe, Zhong, Di, Li, Guozhong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04-03-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 692/4017; 692/617; Animals; Aquaporin 4; Blood-Brain Barrier; Brain injury; Cerebral blood flow; Cerebral Infarction; Edema; Ferroptosis; Gelatinase B; Humanities and Social Sciences; Immunofluorescence; Immunohistochemistry; Inflammation; Ischemia; Ischemic Stroke; Male; Matrix metalloproteinase; Metalloproteinase; Mice; Mice, Inbred C57BL; multidisciplinary; Neurological diseases; NF-E2-Related Factor 2; NRF2; Reperfusion; Reperfusion Injury; Science; Science (multidisciplinary); Stroke; Stroke - drug therapy; Sulforaphane; Therapeutic targets; Zonula occludens-1 protein; Ferroptosis; Inflammation; Ischemic stroke; NRF2; Blood–brain barrier
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-53836-0

Arterial occlusion-induced ischemic stroke (IS) is a highly frequent stroke subtype. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that modulates antioxidant genes. Its role in IS is still unelucidated. The current study focused on constructing a transient middle cerebral artery occlusion (tMCAO) model for investigating the NRF2-related mechanism underlying cerebral ischemia/reperfusion (I/R) injury. Each male C57BL/6 mouse was injected with/with no specific NRF2 activator post-tMCAO. Changes in blood–brain barrier (BBB)-associated molecule levels were analyzed using western-blotting, PCR, immunohistochemistry, and immunofluorescence analysis. NRF2 levels within cerebral I/R model decreased at 24-h post-ischemia. NRF2 activation improved brain edema, infarct volume, and neurological deficits after MCAO/R. Similarly, sulforaphane (SFN) prevented the down-regulated tight junction proteins occludin and zonula occludens 1 (ZO-1) and reduced the up-regulated aquaporin 4 (AQP4) and matrix metalloproteinase 9 (MMP9) after tMCAO. Collectively, NRF2 exerted a critical effect on preserving BBB integrity modulating ferroptosis and inflammation. Because NRF2 is related to BBB injury regulation following cerebral I/R, this provides a potential therapeutic target and throws light on the underlying mechanism for clinically treating IS.