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Neuroscience. 2018 May 21;379:152-166. doi: 10.1016/j.neuroscience.2018.03.008. Epub 2018 Mar 17.

Fisetin Exerts Antioxidant and Neuroprotective Effects in Multiple Mutant hSOD1 Models of Amyotrophic Lateral Sclerosis by Activating ERK.

Author information

1
Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China.
2
Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China.
3
Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China. Electronic address: fenghonglin186@sina.com.

Abstract

Oxidative stress exhibits a central role in the course of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease commonly found to include a copper/zinc superoxide dismutase (SOD1) gene mutation. Fisetin, a natural antioxidant, has shown benefits in varied neurodegenerative diseases. The possible effect of fisetin in ALS has not been clarified as of yet. We investigated whether fisetin affected mutant hSOD1 ALS models. Three different hSOD1-related mutant models were used: Drosophila expressing mutant hSOD1G85R, hSOD1G93A NSC34 cells, and transgenic mice. Fisetin treatment provided neuroprotection as demonstrated by an improved survival rate, attenuated motor impairment, reduced ROS damage and regulated redox homeostasis compared with those in controls. Furthermore, fisetin increased the expression of phosphorylated ERK and upregulated antioxidant factors, which were reversed by MEK/ERK inhibition. Finally, fisetin reduced the levels of both mutant and wild-type hSOD1 in vivo and in vitro, as well as the levels of detergent-insoluble hSOD1 proteins. The results indicate that fisetin protects cells from ROS damage and improves the pathological behaviors caused by oxidative stress in disease models related to SOD1 gene mutations probably by activating ERK, thereby providing a potential treatment for ALS.

KEYWORDS:

ALS; Antioxidant; ERK; fisetin; neurodegeneration; oxidative stress

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