Neuroprotective role of Da Qin Jiu decoction in ischemic stroke: Mitochondrial rescue through PI3K/Akt-mediated UPRmt activation

Jing Luo; Yaling Zheng; Jialei Chen; Xin Xiong; Jiashu Shen; Dou Hong; Ning Jiang; Wenlu Li; Jing Zhao; Jingxian Wu

doi:10.1016/j.jep.2025.119433

Neuroprotective role of Da Qin Jiu decoction in ischemic stroke: Mitochondrial rescue through PI3K/Akt-mediated UPR^mt activation

J Ethnopharmacol. 2025 Mar 13:343:119433. doi: 10.1016/j.jep.2025.119433. Epub 2025 Feb 1.

Authors

Jing Luo¹, Yaling Zheng², Jialei Chen³, Xin Xiong⁴, Jiashu Shen⁵, Dou Hong⁶, Ning Jiang⁷, Wenlu Li⁸, Jing Zhao⁹, Jingxian Wu¹⁰

Affiliations

¹ Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Pathology, Chongqing Medical University, Chongqing, China; Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, China; Department of Pathology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
² Department of Pathology and Pathophysiology, Chongqing Medical University, Chongqing, China.
³ Department of Otolaryngology Head and Neck Surgery, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, China; Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China.
⁴ Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
⁵ Respiratory Medicine Unit and NIHR Oxford BRC, University of Oxford, Oxford, UK.
⁶ Department of Experimental Psychology, University of Oxford, Oxford, UK; Interdisciplinary Bioscience DTP, University of Oxford, Oxford, UK.
⁷ Department of Pathology, Chongqing Medical University, Chongqing, China; Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, China; Department of Pathology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
⁸ Departments of Radiology and Neurology, Neuroprotection Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, USA. Electronic address: wenluli@yahoo.com.
⁹ Department of Pathology and Pathophysiology, Chongqing Medical University, Chongqing, China. Electronic address: jingzhao@cqmu.edu.cn.
¹⁰ Department of Pathology, Chongqing Medical University, Chongqing, China; Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, China; Department of Pathology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: wujingxian@cqmu.edu.cn.

PMID: 39894416
DOI: 10.1016/j.jep.2025.119433

Abstract

Ethnopharmacological relevance: Ischemic stroke (IS) is a highly debilitating neurological condition with limited treatment options and suboptimal outcomes. The traditional Chinese medicine formula Da Qin Jiu Decoction (DQJD) has been widely used for its neuroprotective effects. However, its potential mechanisms of action in IS remain unclear.

Aim of the study: This study aims to investigate the therapeutic effects of DQJD on IS and elucidate its underlying mechanisms of action.

Materials and methods: The neuroprotective effects of DQJD were evaluated in a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R). Neurological recovery was assessed using behavioral tests and tissue analysis, including TTC staining, MRI, and HE & Nissl staining. Mitochondrial function was examined through Western blot, JC-1 assay, ROS staining, and electron microscopy. Additionally, network pharmacology, bioinformatics analyses, and Mendelian randomization were employed to identify key molecular targets and mechanisms. Molecular docking was conducted to explore interactions between active components of DQJD and relevant pathways, focusing on PI3K/Akt signaling.

Results: Treatment with DQJD significantly reduced infarct volume, alleviated tissue damage and improved neurological outcomes. Molecular analyses revealed the upregulation of ATF5 and mitochondrial unfolded protein response (UPR^mt)-related proteins, including HSP60, LONP1, and ClpP, indicating UPR^mt activation. Enhanced mitochondrial membrane potential (ΔΨm), reduced ROS levels, and restoration of mitochondrial dynamics further demonstrated the rescue of mitochondrial function. Network pharmacology and molecular docking analyses highlighted the central role of PI3K/Akt signaling in DQJD-mediated neuroprotection.

Conclusions: DQJD exerts neuroprotective effects in IS by restoring mitochondrial function through UPR^mt activation via the PI3K/Akt pathway. These findings support further exploration of DQJD as a therapeutic option for IS.

Keywords: Da qin jiu decoction; Ischemic stroke; Mendelian randomization; Molecular docking; Network pharmacology; UPR(mt).

MeSH terms

Animals
Disease Models, Animal
Drugs, Chinese Herbal* / pharmacology
Drugs, Chinese Herbal* / therapeutic use
Infarction, Middle Cerebral Artery / drug therapy
Infarction, Middle Cerebral Artery / pathology
Ischemic Stroke* / drug therapy
Ischemic Stroke* / metabolism
Ischemic Stroke* / pathology
Male
Mice
Mice, Inbred C57BL
Mitochondria* / drug effects
Mitochondria* / metabolism
Molecular Docking Simulation
Neuroprotective Agents* / pharmacology
Neuroprotective Agents* / therapeutic use
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Reperfusion Injury / drug therapy
Signal Transduction / drug effects
Unfolded Protein Response* / drug effects

Substances

Proto-Oncogene Proteins c-akt
Neuroprotective Agents
Drugs, Chinese Herbal
Phosphatidylinositol 3-Kinases