AdipoRon Attenuates Neuroinflammation After Intracerebral Hemorrhage Through AdipoR1-AMPK Pathway

Jingwei Zheng; Zeyu Sun; Feng Liang; Weilin Xu; Jianan Lu; Ligen Shi; Anwen Shao; Jun Yu; Jianmin Zhang

doi:10.1016/j.neuroscience.2019.05.060

AdipoRon Attenuates Neuroinflammation After Intracerebral Hemorrhage Through AdipoR1-AMPK Pathway

Neuroscience. 2019 Aug 1:412:116-130. doi: 10.1016/j.neuroscience.2019.05.060. Epub 2019 Jun 7.

Authors

Jingwei Zheng¹, Zeyu Sun², Feng Liang³, Weilin Xu⁴, Jianan Lu⁵, Ligen Shi⁶, Anwen Shao⁷, Jun Yu⁸, Jianmin Zhang⁹

Affiliations

¹ Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: 21618221@zju.edu.cn.
² Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: 11718342@zju.edu.cn.
³ Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: frankfeng@zju.edu.cn.
⁴ Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: 11618330@zju.edu.cn.
⁵ Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: 21718267@zju.edu.cn.
⁶ Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: 11618216@zju.edu.cn.
⁷ Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: 21118116@zju.edu.cn.
⁸ Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: 2505020@zju.edu.cn.
⁹ Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Brain Research Institute, Zhejiang University, Hangzhou, Zhejiang, China; Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: zjm135@zju.edu.cn.

PMID: 31176703
DOI: 10.1016/j.neuroscience.2019.05.060

Abstract

Neuroinflammation is considered to be a critical component in the pathological process after intracerebral hemorrhage (ICH). Microglia are the foremost and earliest inflammatory cells participating in the pathological process of ICH. AdipoRon is the agonist of AdipoR1 (Adiponectin receptor 1), which enhances P-AMPK (phosphorylated AMP-activated protein kinase) activation. The activated AMPK facilitates microglia/macrophage polarization by driving the cell state from pro-inflammatory M1 state to anti-inflammatory M2 state. The study aims to investigate the role of AdipoRon in microglial polarization and neuroprotection after ICH. The experimental ICH model was established by autologous blood injection, and the treated group was done additionally by intraperitoneal injection of drugs. Flow cytometry analysis and immunofluorescence staining were performed to quantify the ratio of M1 to M2 phenotype microglia in mice. The present study indicated that AdipoRon could ameliorate neurological deficits in mice after ICH. Flow cytometric analysis demonstrated that the proportion of CD206⁺ cells to CD45^+low CD11b⁺ cells (microglia isolated from the brain tissue of mice) was increased after AdipoRon treatment. AdipoR1 siRNA and AMPK inhibitor could reverse the positive effects of AdipoRon. AdipoR1 and P-AMPK expression was also significantly increased after AdipoRon treatment. The in vitro experiment showed that AdipoRon not only directly inhibited neuronal ROS overproduction, but also indirectly decreased the neuronal death in a transwell co-culture system. In summary, AdipoRon protects against ICH induced injury through promoting M2a microglia polarization and reducing neuronal death. These effects of AdipoRon rely on the activation of AdipoR1-AMPK signaling pathway.

Keywords: ICH; adipoRon; inflammation; microglia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenylate Kinase / metabolism*
Animals
Anti-Inflammatory Agents / pharmacology
Anti-Inflammatory Agents / therapeutic use*
Cerebral Hemorrhage / complications
Cerebral Hemorrhage / drug therapy*
Cerebral Hemorrhage / metabolism
Disease Models, Animal
Encephalitis / drug therapy*
Encephalitis / etiology
Encephalitis / metabolism
Male
Mice
Neurons / drug effects
Neurons / metabolism
Phosphorylation
Piperidines / pharmacology
Piperidines / therapeutic use*
Receptors, Adiponectin / metabolism*
Signal Transduction / drug effects*

Substances

AdipoRon
Anti-Inflammatory Agents
Piperidines
Receptors, Adiponectin
adiponectin receptor 1, mouse
Adenylate Kinase