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PLoS One. 2017 Nov 6;12(11):e0187215. doi: 10.1371/journal.pone.0187215. eCollection 2017.

Febuxostat ameliorates secondary progressive experimental autoimmune encephalomyelitis by restoring mitochondrial energy production in a GOT2-dependent manner.

Author information

1
Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
2
Department of Neurology, Osaka General Medical Center, Osaka, Osaka, Japan.
3
Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
4
Pharmaceutical Development Research Laboratories, Teijin Pharma Ltd., Hino, Tokyo, Japan.
5
Department of Neurology, National Hospital Organization Toneyama National Hospital, Toyonaka, Osaka, Japan.

Abstract

Oxidative stress and mitochondrial dysfunction are important determinants of neurodegeneration in secondary progressive multiple sclerosis (SPMS). We previously showed that febuxostat, a xanthine oxidase inhibitor, ameliorated both relapsing-remitting and secondary progressive experimental autoimmune encephalomyelitis (EAE) by preventing neurodegeneration in mice. In this study, we investigated how febuxostat protects neuron in secondary progressive EAE. A DNA microarray analysis revealed that febuxostat treatment increased the CNS expression of several mitochondria-related genes in EAE mice, most notably including GOT2, which encodes glutamate oxaloacetate transaminase 2 (GOT2). GOT2 is a mitochondrial enzyme that oxidizes glutamate to produce α-ketoglutarate for the Krebs cycle, eventually leading to the production of adenosine triphosphate (ATP). Whereas GOT2 expression was decreased in the spinal cord during the chronic progressive phase of EAE, febuxostat-treated EAE mice showed increased GOT2 expression. Moreover, febuxostat treatment of Neuro2a cells in vitro ameliorated ATP exhaustion induced by rotenone application. The ability of febuxostat to preserve ATP production in the presence of rotenone was significantly reduced by GOT2 siRNA. GOT2-mediated ATP synthesis may be a pivotal mechanism underlying the protective effect of febuxostat against neurodegeneration in EAE. Accordingly, febuxostat may also have clinical utility as a disease-modifying drug in SPMS.

PMID:
29107957
PMCID:
PMC5673182
DOI:
10.1371/journal.pone.0187215
[Indexed for MEDLINE]
Free PMC Article

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