15, 16-Dihydrotanshinone I protects against ischemic stroke by inhibiting ferroptosis via the activation of nuclear factor erythroid 2-related factor 2

Chuanhong Wu; Feipeng Duan; Ruocong Yang; Yaolan Dai; Xiuping Chen; Shaojing Li

doi:10.1016/j.phymed.2023.154790

15, 16-Dihydrotanshinone I protects against ischemic stroke by inhibiting ferroptosis via the activation of nuclear factor erythroid 2-related factor 2

Phytomedicine. 2023 Jun:114:154790. doi: 10.1016/j.phymed.2023.154790. Epub 2023 Mar 30.

Authors

Chuanhong Wu¹, Feipeng Duan², Ruocong Yang², Yaolan Dai², Xiuping Chen³, Shaojing Li⁴

Affiliations

¹ 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.
² Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
³ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao, China. Electronic address: xpchen@um.edu.mo.
⁴ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China. Electronic address: shaojingli2004@126.com.

PMID: 37028247
DOI: 10.1016/j.phymed.2023.154790

Abstract

Background: 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.

Purpose: This study aimed to investigate the protective effect of DHT against ischemic stroke and its underlying mechanism.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: 15, 16-Dihydrotanshinone I; Ferroptosis; Ischemic stroke; Nuclear factor erythroid 2-related factor 2.

MeSH terms

Animals
Ferroptosis*
Infarction, Middle Cerebral Artery
Ischemic Stroke*
NF-E2-Related Factor 2 / metabolism
Rats
Signal Transduction

Substances

dihydrotanshinone I
NF-E2-Related Factor 2