?-Caryophyllene suppresses ferroptosis induced by cerebral ischemia reperfusion via activation of the NRF2/HO-1 signaling pathway in MCAO/ R rats

作者全名："Hu, Qingwen; Zuo, Tianrui; Deng, Ling; Chen, Sha; Liu, Shengwei; Liu, JingDong; Wang, Xuan; Fan, Xiaomei; Dong, Zhi"

作者地址："[Hu, Qingwen; Zuo, Tianrui; Deng, Ling; Chen, Sha; Liu, Shengwei; Liu, JingDong; Wang, Xuan; Fan, Xiaomei; Dong, Zhi] Chongqing Med Univ, Coll Pharm, Chongqing 400016, Peoples R China"

通信作者："Dong, Z (通讯作者)，Chongqing Med Univ, Coll Pharm, Chongqing 400016, Peoples R China."

来源：PHYTOMEDICINE

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000820069300002

JCR分区：Q1

影响因子：7.9

年份：2022

卷号：102

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Cerebral-ischemia reperfusion; ?-Caryophyllene; Ferroptosis; NRF2; HO-1

摘要："Background: Ischemic stroke is a complex brain disease regulated by several cell death processes, including apoptosis, autophagy, and ferroptosis. beta-Caryophyllene (BCP), a natural bicyclic sesquiterpene abundantly found in essential oils, has been demonstrated to have potential pharmacological benefits in many diseases, including ischemic stroke. Purpose: This research was to determine the existence of ferroptosis in the pathogenesis of acute ischemic stroke and investigate whether BCP can inhibit ferroptosis to improve cerebral ischemia injury by activating the NRF2/ HO-1 signaling pathway in rats. Methods: First, we verified ferroptosis by assessing proferroptotic changes after middle cerebral artery occlusion reperfusion (MCAO/R), along with protein and lipid peroxidation levels. Then male rats were divided randomly into Sham, MCAO/R, ML385 (NRF2-specific inhibitor) and BCP groups. The effects of BCP on cerebral injury were detected by the modified neurological severity score, TTC staining, and hematoxylin-eosin staining. We conducted western blotting analyzes of proteins, including those involved in ferroptosis and related signaling pathways. To demonstrate the neuroprotective effect of BCP in vitro, primary astrocytes were pretreated with different concentrations of BCP (10, 20, and 40 mu M) for 24 h before oxygen-glucose deprivation/re-oxygenation (ODG/R). Results: We concluded that ferroptosis was engaged in the process of I/R-induced neurological damage, implying that this novel type of cell death might provide new therapeutic options for the clinical treatment of ischemic stroke. In vivo study proved that BCP improved neurological scores, infarct volume, and pathological features after MCAO/R. We demonstrated that BCP evidently enhanced NRF2 nuclear translocation, activated the NRF2/ HO-1 pathway, which protected against ferroptosis. In vitro investigation revealed the same results. BCP decreased OGD/R-induced ROS generation and iron accumulation. Furthermore, the neuroprotective effects of BCP were reversed by the NRF2 inhibitor ML385. Conclusion: Our results indicated the critical role of ferroptosis in cerebral I/R injury. For the first time, we showed that the significant neuroprotective effects of BCP in attenuating ischemic stroke injury are correlated with ferroptosis regulation, and its mechanism is associated with activation of the NRF2/HO-1 axis."

基金机构：Chongqing Natural Science Foun-dation [cstc2018jcyjAX0378]; Chongqing Basic Research and Frontier Exploration Special Project [20210121]

基金资助正文：Acknowledgments This study was supported by the Chongqing Natural Science Foun-dation (No. cstc2018jcyjAX0378) and the Chongqing Basic Research and Frontier Exploration Special Project (No. 20210121)