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Wogonin Accelerates Hematoma Clearance and Improves Neurological Outcome via the PPAR-γ Pathway After Intracerebral Hemorrhage

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Abstract

Intracerebral hemorrhage (ICH) is a cerebrovascular disease with high mortality and morbidity for which effective treatments are currently lacking. Wogonin is a major flavonoid compound isolated from Scutellaria radix. Accumulating evidence suggests that wogonin plays a crucial role in anti-inflammatory and anti-oxidative stress. Treatment of microglia with nuclear receptor agonists augments the expression of phagocytosis-related genes. However, the neuroprotective effects of wogonin in ICH remain obscure. In this study, we elucidated an innovative mechanism by which wogonin acts to enhance phagocytosis in a murine model of ICH. Wogonin promoted hematoma clearance and improved neurological recovery after ICH by upregulating the expression of Axl, MerTK, CD36, and LAMP2 in perihematomal microglia and BV2 cells. Treatment of a murine model of ICH with wogonin stimulated microglial phagocytosis in vitro. Further, we demonstrated that wogonin dramatically attenuated inflammatory and oxidative stress responses in a murine model of ICH by reducing the expression of pro-inflammatory cytokines and pro-oxidant enzymes such as TNF-α, IL-1β, and inducible nitric oxide synthase (iNOS) after ICH. The effects of wogonin were abolished by administration of the PPAR-γ inhibitor GW9662. In conclusion, our data suggest that wogonin facilitates hematoma clearance and neurobehavioral recovery by targeting PPAR-γ.

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Data Availability

All raw data used in this manuscript are available on reasonable request.

Abbreviations

iNOS:

Inducible nitric oxide synthase

ICH:

Intracerebral hemorrhage

CNS:

Central nervous system

PPAR-γ:

Peroxisome proliferator-activated receptor-γ

TAM:

Tyro3, Axl and MerTK

LAMP2:

Lysosomal associated membrane protein 2

ROS:

Reactive oxygen species

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Funding

This study was supported by the National Natural Science Foundation of China (No. 81571106, 81771246, 81971099, 81870908, 81801144, 81870910), National Key R&D Program of China (2018YFC1312600, 2018YFC1312603), Key Research and Development Project of Zhejiang Province (No.2018C03011), Natural Science Foundation of Zhejiang Province (LQ20H090015), Innovative Talents Plan of Zhejiang Province (2020380752), Scientific Research Fund of Zhejiang Provincial Education Department (No. Y201941838), and Medical and Health Scientific Research Project of Zhejiang Province (2018KY408).

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  1. Jianfeng Zhuang, Yucong Peng and Chi Gu contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road 88th, Hangzhou, China

    Jianfeng Zhuang, Yucong Peng, Chi Gu, Huihui Chen, Zheng Lin, Hang Zhou, Jianru Li, Xiaobo Yu, Yang Cao, Hanhai Zeng, Xiongjie Fu, Chaoran Xu, Shenglong Cao, Chun Wang, Feng Yan & Gao Chen

  2. Department of Radiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

    Xiao Wu & Peiyu Huang

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Contributions

JFZ and YCP performed the ICH model and immunofluorescence staining. CG performed drug administration. HZ performed flow cytometry. JRL performed behavioral tests. XW and PYH performed the MRI. CRX and SLC performed western blots. HHZ and HHC performed immunohistochemistry staining. XJF and CW performed qRT-PCR. YC performed cell culture. XBY and ZL performed data analysis. GC and FY conceived and designed experiments. JFZ and YCP wrote and edited the manuscript. All authors corrected and approved the final manuscript version.

Corresponding authors

Correspondence to Feng Yan or Gao Chen.

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The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This study was carried out in accordance with the recommendations of institutional guidelines of the Care and Use of Laboratory Animals of the National Institutes of Health and was approved by the Institutional Animal Care and Use Committee of Zhejiang University.

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Supplementary Figure 1

Experimental design and grouping. A-E: The experimental design and animal grouping in vivo; F-H: The experimental design and cell grouping in vitro. (PNG 39593 kb)

High resolution image (TIF 2997 kb)

Supplementary Figure 2

The expression of PPAR-γ over time after ICH. (A) Western blot for PPAR-γ proteins expression at different time points after ICH. (B) Statistical analysis of PPAR-γ protein. Values are expressed as mean ± SD. n = 6 for each group, *P < 0.05, vs Sham. (PNG 1206 kb)

High resolution image (TIF 212 kb)

Supplementary Figure 3

Distribution of Axl and MerTK after ICH. A-C: Immunofluorescence double label images showed that Axl (red) were mainly located in microglia (green) rather than neuron (green) and astrocyte (green) at day 3 after ICH; D-F: Immunofluorescence double label images showed that MerTK (red) were mainly located in microglia (green) rather than neuron (green) and astrocyte (green) at day 3 after ICH (scale bars: 50 μm). (PNG 5219 kb)

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Zhuang, J., Peng, Y., Gu, C. et al. Wogonin Accelerates Hematoma Clearance and Improves Neurological Outcome via the PPAR-γ Pathway After Intracerebral Hemorrhage. Transl. Stroke Res. 12, 660–675 (2021). https://doi.org/10.1007/s12975-020-00842-9

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