2. Academic Validation
  3. Dihydromyricetin attenuates intracerebral hemorrhage by reversing the effect of LCN2 via the system Xc- pathway

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.
Xia Liu 1,  Yunjie Li 1,  Shiling Chen 1,  Jingfei Yang 2,  Jie Jing 3,  Jiarui Li 1,  Xuan Wu 1,  Jiahui Wang 1,  Jingyi Wang 1,  Ge Zhang 1,  Zhouping Tang 4,  Hao Nie 5
Affiliations

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: [email protected].
  • 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: [email protected].
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-.

Figures
Products