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Cell Mol Neurobiol. 2019 Apr 24. doi: 10.1007/s10571-019-00675-7. [Epub ahead of print]

Berberine Facilitates Angiogenesis Against Ischemic Stroke Through Modulating Microglial Polarization via AMPK Signaling.

Zhu J1,2, Cao D1,2, Guo C3, Liu M1,2, Tao Y1, Zhou J4, Wang F5, Zhao Y1,2, Wei J6, Zhang Y7,8, Fang W9, Li Y10.

Author information

1
Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, People's Republic of China.
2
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
3
Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, 710000, People's Republic of China.
4
Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, People's Republic of China.
5
Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, People's Republic of China.
6
Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, People's Republic of China.
7
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. zhangyingdong@aliyun.com.
8
Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, People's Republic of China. zhangyingdong@aliyun.com.
9
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. weirongfang@163.com.
10
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China. yunmanli@cpu.edu.cn.

Abstract

Evidence suggests that microglia/macrophages can change their phenotype to M1 or M2 and participate in tissue damage or repair. Berberine (BBR) has shown promise in experimental stroke models, but its effects on microglial polarization and long-term recovery after stroke are elusive. Here, we investigated the effects of BBR on angiogenesis and microglial polarization through AMPK signaling after stroke. In the present study, C57BL/6 mice were subjected to transient middle cerebral artery occlusion (tMCAO), intragastrically administrated with BBR at 50 mg/kg/day. Neo-angiogenesis was observed by 68Ga-NODAGA-RGD micro-PET/CT and immunohistochemistry. Immunofluorescent staining further exhibited an increase of M2 microglia and a reduction of M1 microglia at 14 days after stroke. In vitro studies, the lipopolysaccharide (LPS)-induced BV2 microglial cells were used to confirm the AMPK activation effect of BBR. RT-PCR, Flow cytometry, and ELISA all demonstrated that BBR could inhibit M1 polarization and promote M2 polarization. Furthermore, treatment of human umbilical vein endothelial cells (HUVEC) with conditioned media collected from BBR-treated BV2 cells promoted angiogenesis. All effects stated above were reversed by AMPK inhibitor (Compound C) and AMPK siRNA. In conclusion, BBR treatment improves functional recovery and promotes angiogenesis following tMCAO via AMPK-dependent microglial M2 polarization.

KEYWORDS:

Angiogenesis; Berberine; Ischemic Stroke; Microglia/macrophages; Polarization

PMID:
31020571
DOI:
10.1007/s10571-019-00675-7

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