Classical prescription Daqinjiao decoction inhibit cerebral ischemia/reperfusion induced necroptosis and ferroptosis through multiple mechanisms

Yuwen Liu; Jiping Liu; Naping Hu; Zhengrong Li; Anqi Liu; Ruyue Luo; Siyu Du; Dongyan Guo; Jiankang Li; Jialin Duan

doi:10.1016/j.jep.2024.119300

Classical prescription Daqinjiao decoction inhibit cerebral ischemia/reperfusion induced necroptosis and ferroptosis through multiple mechanisms

J Ethnopharmacol. 2024 Dec 28:340:119300. doi: 10.1016/j.jep.2024.119300. Online ahead of print.

Authors

Yuwen Liu¹, Jiping Liu², Naping Hu³, Zhengrong Li¹, Anqi Liu¹, Ruyue Luo¹, Siyu Du¹, Dongyan Guo⁴, Jiankang Li⁵, Jialin Duan⁶

Affiliations

¹ Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi, 710072, China.
² The Key Laboratory of Basic and New Drug Research of Traditional Chinese Medicine, Shaanxi University of Chinese Medicine, Xi'an, 712046, Shaanxi, China.
³ General Hospital of Xinjiang Production and Construction Corps, Department of Pharmacy, 232 Qingnian Road, Tianshan District, Xinjiang Uygur Autonomous Region, Urumqi City, 830092, China.
⁴ The Key Laboratory of Basic and New Drug Research of Traditional Chinese Medicine, Shaanxi University of Chinese Medicine, Xi'an, 712046, Shaanxi, China. Electronic address: xmc2051080@163.com.
⁵ Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi, 710072, China. Electronic address: lijiankang-1025@nwpu.edu.cn.
⁶ Xi'an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi, 710072, China. Electronic address: duanjl@nwpu.edu.cn.

PMID: 39736347
DOI: 10.1016/j.jep.2024.119300

Abstract

Ethnopharmacological relevance: The Daqinjiao decoction (DQJT), a classical prescription, has been utilized for millennia in stroke management, yet its underlying mechanisms remained obscure.

Aim of the study: The aim of this study was to elucidate the mechanisms through which DQJT mitigates cerebral ischemia/reperfusion injury (CI/RI).

Materials and methods: The quantification of DQJT's primary components were performed by HPLC. Pharmacological assessments were then conducted to ascertain DQJT's efficacy in a Middle Cerebral Artery Occlusion/Reperfusion (MCAO/R) model. Following this, untargeted metabolomics, lipidomics and network pharmacology analyses were undertaken to unveil potential mechanisms, which were subsequently validated. UPLC-Q-TOF/MS was utilized to detect DQJT-derived chemicals in brain tissue, and molecular docking techniques were employed to investigate the bioactive compounds.

Results: DQJT treatment reduced brain damage induced by MCAO/R, as evidenced by decreased infarct sizes, enhanced behavioral function scores, and diminished neuronal damages. Untargeted metabolomics and lipidomics revealed that DQJT improved metabolism of unsaturated fatty acids. According to network pharmacology, lipid metabolism, cAMP signaling pathway and toll-like receptor signaling pathway pathways were notably affected, with HSP90AA1, TLR4, and PKA identified as potential targets of DQJT. Immunofluorescence and Western blot analyses further demonstrated that DQJT counteracted necroptosis and ferroptosis by inhibiting the HSP90AA1 and TLR4 pathways and enhancing the PKA pathway. Molecular docking results supported that the possible pharmacodynamic substances of DQJT in protecting against CI/RI.

Conclusion: This research established that DQJT attenuates brain injury induced by MCAO/R through the modulation of necroptosis and ferroptosis via pathways including HSP90AA1, TLR4, and PKA. It shed light on the potential mechanisms and effective constituents of DQJT in stroke treatment, paving the way for further exploration of this ancient formula.

Keywords: Daqinjiao decoction; Ferroptosis; MCAO/R; Necroptosis.