Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao, China; The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes) & the Affiliated Hospital of Qingdao University, Qingdao, China.
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
Phytomedicine. 2023 Jun;114:154790. doi: 10.1016/j.phymed.2023.154790. Epub 2023 Mar 30.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of antioxidative stress responses, which are associated with ferroptosis inhibition. Ferroptosis is closely related to the pathophysiological process of ischemic stroke. 15, 16-Dihydrotanshinone I (DHT), a lipophilic tanshinone extracted from the root of Salvia miltiorrhiza Bunge (Danshen), has various pharmacological effects. However, its effect against ischemic stroke remains to be examined.
This study aimed to investigate the protective effect of DHT against ischemic stroke and its underlying mechanism.
Rats with permanent middle cerebral artery occlusion (pMCAO)-induced cerebral ischemia rats and tert-butyl hydroperoxide (t-BHP)-injured PC12 cells were used to investigate the protective effect of DHT against ischemic stroke effect and the potential mechanism.
The results showed that DHT decreased ferroptosis in-vitro experiment, as indicated by decreased lipid ROS generation, increased Gpx4 expression and the ratio of GSH/GSSG, and improved mitochondrial function. The inhibitory effect of DHT on ferroptosis was decreased after Nrf2 silencing. Furthermore, DHT decreased the neurological score, infarct volume, and cerebral edema, increased regional cerebral blood flow, and improved the microstructure of white-grey matter in pMCAO rats. In addition, DHT activated Nrf2 signaling and inhibited ferroptosis marker events. Nrf2 activator and ferroptosis inhibitor also exerted protective effects on pMCAO rats.
These data demonstrated that DHT might have therapeutic potential for ischemic stroke and protects against ferroptosis via the activation of Nrf2. This study provides new insight into DHT-mediated prevention of ferroptosis in ischemic stroke.
核因子红细胞 2 相关因子 2（Nrf2）是抗氧化应激反应的关键调节因子，与抑制铁死亡有关。铁死亡与缺血性中风的病理生理过程密切相关。15,16-二氢丹参酮 I（DHT）是从丹参根中提取的一种亲脂性丹参酮，具有多种药理作用。然而，其对缺血性中风的作用仍需进一步研究。
本研究旨在探讨 DHT 对缺血性中风的保护作用及其潜在机制。
采用永久性大脑中动脉闭塞（pMCAO）诱导的脑缺血大鼠和叔丁基过氧化氢（t-BHP）损伤的 PC12 细胞，研究 DHT 对缺血性中风的保护作用及其潜在机制。
结果表明，DHT 降低了体外实验中的铁死亡，表现为脂质 ROS 生成减少、Gpx4 表达增加和 GSH/GSSG 比值增加，以及线粒体功能改善。Nrf2 沉默后，DHT 抑制铁死亡的作用减弱。此外，DHT 降低了 pMCAO 大鼠的神经评分、梗死体积和脑水肿，增加了局部脑血流量，并改善了白质-灰质的微观结构。此外，DHT 激活了 Nrf2 信号通路并抑制了铁死亡标志物事件。Nrf2 激活剂和铁死亡抑制剂对 pMCAO 大鼠也有保护作用。
这些数据表明，DHT 可能对缺血性中风具有治疗潜力，并通过激活 Nrf2 来保护铁死亡。本研究为 DHT 介导的缺血性中风中铁死亡的预防提供了新的见解。
