期刊
PLOS ONE
卷 13, 期 5, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0195968
关键词
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资金
- Korea Health 21 R&D Project by the Ministry of Health & Welfare, Republic of Korea [HI14C2348]
- Brain Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT & Future Planning [800-20170122, 2016M3C7A1914002]
- National Research Foundation of Korea [2015R1D1A1A01060056]
- Seoul National University Hospital [26-2017-0030]
- Korea Brain Research Institute [800-20170122]
- SNUH research fund [26-2017-0030]
Huntington's disease (HD) is one of the most devastating genetic neurodegenerative disorders with no effective medical therapy. beta-Lapachone (beta L) is a natural compound obtained from the bark of the Lapacho tree and has been reported to have beneficial effects on various diseases. Sirt1 is a deacetylase of the sirtuin family and deacetylates proteins including the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) which is associated with mitochondrial respiration and biogenesis. To examine the effectiveness of beta L on HD, beta L was orally applied to R6/2 HD mice and behavioral phenotypes associated with HD, such as impairment of rota-rod performance and increase of clasping behavior, as well as changes of Sirt1 expression, CREB phosphorylation and PGC-1 alpha deacetylation were examined. Western blot results showed that Sirt1 and p-CREB levels were significantly increased in the brains of beta L-treated R6/2 mice. An increase in deacetylation of PGC-1 alpha, which is thought to increase its activity, was observed by oral administration of beta L. In an in vitro HD model, beta L treatment resulted in an attenuation of MitoSOX red fluorescence intensity, indicating an amelioration of mitochondrial reactive oxygen species by beta L. Furthermore, improvements in the rota-rod performance and clasping score were observed in R6/2 HD mice after oral administration of beta L compared to that of vehicle control-treated mice. Taken together, our data show that beta L is a potential therapeutic candidate for the treatment of HD-associated phenotypes, and increases in Sirt1 level, CREB phosphorylation and PGC-103B1 deacetylation can be the possible underlying mechanism of the effects of beta L.
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