Journal of Shanghai Jiao Tong University (Medical Science) >

2022 , Vol. 42 >Issue 9: 1265 - 1274

DOI: https://doi.org/10.3969/j.issn.1674-8115.2022.09.013

Basic research

Effect of α-mangostin on amyotrophic lateral sclerosis and its mechanism

  • Dayuan WANG ,
  • Jianrong XU ,
  • Gan JIANG ,
  • Qingxiang SONG ,
  • Jun CHEN ,
  • Huahua SONG ,
  • Xiao GU ,
  • Xiaoling GAO
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  • 1.Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
    2.Fudan University School of Pharmacy, Shanghai 201203, China
GAO Xiaoling, E-mail: shellygao1@sjtu.edu.cn.

Received date: 2022-05-29

  Accepted date: 2022-08-24

  Online published: 2022-09-17

Supported by

National Natural Science Foundation of China(81722043);Innovative Research Team of High-Level Local Universities in Shanghai(SHSMU-ZDCX20211201)

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Abstract

Objective ·To study the effect of α-mangostin (AM) on the superoxide dismutase 1 (SOD1) mutant amyotrophic lateral sclerosis (ALS) and the possible mechanism. Methods ·The ATP level in the microglia was measured by kits to investigate the effect of AM on the energy balance in the SOD1 aggregates-treated microglia (SOD1-ALS model microglia). Western blotting was used to detect the activation levels of AMP-activated protein kinase (AMPK) and the key molecules in its metabolic regulation pathway including liver kinase B1 and PPARγ coactivator 1α, in order to explore the regulatory role of AM on AMPK pathway in the disease-associated microglia. The ATP level was also detected after AMPK activation being inhibited by compound C to explore the role of AMPK in the regulation of energy balance by AM in the SOD1-ALS microglia. The microglial uptake and degradation of SOD1 aggregates was detected by using ELISA with or without inhibition of AMPK activation, to explore the role of AMPK-mediated energy regulation in AM regulating SOD1 clearance in the disease-associated microglia. Western blotting and immunofluorescence were used to study the effect of AM on microglial autophagy and the role of autophagy in AM regulating the degradation of SOD1 in the microglia. AM-encapsulated nanoparticles (NPAMs) were prepared to realize the in vivo treatment of AM. NPAMs were injected into the SOD1*G93A ALS model mice through the caudal vein for 30 d, once a day. SOD1 aggregates were detected by immunohistochemistry in the lumbar spinal cords of the ALS mice. Neuronal damage and loss were measured by using Nissl staining and anti-NeuN immunohistochemistry. Motor ability of the ALS mice was evaluated by rotarod test and hindlimb clasping test. Disease progress of the ALS mice was evaluated by recording body mass and survival time. Results ·AM increased the ATP level in the diseased-associated microglia and enhanced microglial phagocytosis and autophagy-mediated degradation of SOD1 aggregates. While inhibiting AMPK pathway abolished these effects of AM, NPAM reduced SOD1 aggregates in the lumbar spinal cord of the SOD1*G93A ALS model mice, and reduced the neuron damage and loss. NPAM also alleviated the body mass loss and the damaged motor ability of the ALS mice. Conclusion ·AM enhances microglial clearance of SOD1 aggregates through AMPK-mediated recovery of energy balance, and thus alleviates the neuropathological changes and symptoms in ALS mice.

Key words： amyotrophic lateral sclerosis (ALS); α-mangostin (AM); microglia; superoxide dismutase 1 (SOD1); energy balance; AMP activated protein kinase (AMPK)

Cite this article

Dayuan WANG , Jianrong XU , Gan JIANG , Qingxiang SONG , Jun CHEN , Huahua SONG , Xiao GU , Xiaoling GAO . Effect of α-mangostin on amyotrophic lateral sclerosis and its mechanism[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022 , 42(9) : 1265 -1274 . DOI: 10.3969/j.issn.1674-8115.2022.09.013

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