Neuroprotective effect of Dl-3-n-butylphthalide against ischemia–reperfusion injury is mediated by ferroptosis regulation via the SLC7A11/GSH/GPX4 pathway and the attenuation of blood–brain barrier disruption

Frontiers in Aging Neuroscience

Aging Neuroscience

Xiaojun Zhang¹  E. Lv²  Xiangling Li³  Yanqiang Wang⁴  Xuewei Li⁴  Shuangli Xu⁵  Youkui Shi⁵  Yutian Li⁶ 

[1] Department II of Neurology, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China;Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong, China;Department of Internal Medicine, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China;Department of Rheumatology, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China;Emergency Department, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China;School of Pharmacy, Weifang Medical University, Weifang, Shandong, China;

关键词: N-butylphthalide;    ischemic/reperfusion;    ferroptosis;    blood–brain barrier;    neuroinflammation;   

DOI  :  10.3389/fnagi.2023.1028178

 received in 2022-08-25, accepted in 2023-02-07,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundStroke is one of the most severe diseases worldwide, resulting in physical and mental problems. Dl-3-n-butylphthalide, a compound derived from celery seed, has been approved for treating ischemic stroke in China. No study has evaluated how Dl-3-n-butylphthalide affects the ferroptosis SLC7A11/GSH/GPX4 signal pathway and blood–brain barrier (BBB) PDGFRβ/PI3K/Akt signal pathways in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model of ischemic stroke.MethodsSprague–Dawley rats were used to develop the MCAO/R model. Our study used three incremental doses (10, 20, and 30) of Dl-3-n-butylphthalide injected intraperitoneally 24 h after MCAO/R surgery. The neuroprotective effect and success of the model were evaluated using the neurofunction score, brain water content determination, and triphenyl-tetrazolium chloride-determined infarction area changes. Pathological changes in the brain tissue and the degree of apoptosis were examined by hematoxylin and eosin, Nissl, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. In addition, pathway proteins and RNA expression levels were studied to verify the effects of Dl-3-n-butyphthalide on both pathways. At the same time, commercial kits were used to detect glutathione, reactive oxygen species, and malondialdehyde, to detect oxidative stress in brain tissues.ResultsThe middle dose of Dl-3-n-butylphthalide not only improved MCAO-induced brain dysfunction and alleviated pathological damage, brain inflammatory response, oxidative stress, and apoptosis but also protected against ferroptosis and reduced BBB damage. These changes resulted in improved neurological function in the cerebral cortex.ConclusionWe speculate that Dl-3-n-butylphthalide has a neuroprotective effect on focal cerebral ischemia/reperfusion, which may be mediated through ferroptosis-dependent SLC7A11/GSH/GPX4 signal pathway and PDGFRβ/PI3/Akt signal pathway.

【 授权许可】

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Copyright © 2023 Xu, Li, Li, Li, Lv, Zhang, Shi and Wang.