Dihydromyricetin attenuates intracerebral hemorrhage by reversing the effect of LCN2 via the system Xc- pathway

Xia Liu; Yunjie Li; Shiling Chen; Jingfei Yang; Jie Jing; Jiarui Li; Xuan Wu; Jiahui Wang; Jingyi Wang; Ge Zhang; Zhouping Tang; Hao Nie

doi:10.1016/j.phymed.2023.154756

Dihydromyricetin attenuates intracerebral hemorrhage by reversing the effect of LCN2 via the system Xc- pathway

Phytomedicine. 2023 Jul:115:154756. doi: 10.1016/j.phymed.2023.154756. Epub 2023 Mar 12.

Authors

Xia Liu¹, Yunjie Li¹, Shiling Chen¹, Jingfei Yang², Jie Jing³, Jiarui Li¹, Xuan Wu¹, Jiahui Wang¹, Jingyi Wang¹, Ge Zhang¹, Zhouping Tang⁴, Hao Nie⁵

Affiliations

¹ Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, China.
² Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, China.
³ Department of Neurology, Qilu Hospital, Shandong University, Jinan, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, China.
⁴ Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, China. Electronic address: ddjtzp@163.com.
⁵ Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, China. Electronic address: haonie@tjh.tjmu.edu.cn.

PMID: 37130481
DOI: 10.1016/j.phymed.2023.154756

Abstract

Background: The limited understanding of the pathological mechanisms of intracerebral hemorrhage (ICH) and the absence of successful therapies lead to poor prognoses for patients with ICH. Dihydromyricetin (DMY) has many physiological functions, such as regulating lipid and glucose metabolism and modulating tumorigenesis. Moreover, DMY has been proven to be an effective treatment of neuroprotection. However, no reports to date have been made regarding the impact of DMY on ICH.

Purpose: This investigation aimed to identify the role of DMY on ICH in mice and the underlying mechanisms.

Methods/results: This study demonstrated that DMY treatment effectively reduced hematoma size and cell apoptosis of brain tissue, and improved neurobehavioral outcomes in mice with ICH. Transcriptional and network pharmacological analyses revealed that lipocalin-2 (LCN2) was a potential target of DMY in ICH. After ICH, LCN2 mRNA and protein expression in brain tissue increased and DMY could inhibit the expression of LCN2. The rescue experiment with the implementation of LCN2 overexpression verified these observations. Furthermore, after DMY treatment, there was a significant decrease in cyclooxygenase 2 (COX2), phospho-extracellular regulated protein kinase (P-ERK), iron deposition, and the number of abnormal mitochondria, which were reversed by the overexpression of LCN2. Proteomics analysis suggests that SLC3A2 may be the downstream target of LCN2, promoting ferroptosis. Finally, LCN2 was shown to bind to SLC3A2 and regulate the downstream glutathione (GSH) synthesis and Glutathione Peroxidase 4 (GPX4) expression and glutathione (GSH) synthesis, as determined by molecular docking and co-immunoprecipitation analysis.

Conclusion: Our study confirmed for the first time that DMY might offer a favorable treatment for ICH through its action on LCN2. The possible mechanism for this could be that DMY reverses the inhibitory effect of LCN2 on the system Xc-, lessening ferroptosis in brain tissue. The findings of this study offer a greater understanding of how DMY affects ICH at a molecular level and could be conducive to developing therapeutic targets for ICH.

Keywords: Dihydromyricetin; Ferroptosis; Intracerebral hemorrhage; Lipocalin 2; System Xc-.

MeSH terms

Animals
Cerebral Hemorrhage* / drug therapy
Glutathione* / metabolism
Lipocalin-2
Mice
Molecular Docking Simulation

Substances

Lipocalin-2
dihydromyricetin
Glutathione
Lcn2 protein, mouse