Amelioration of Huntington's disease phenotypes by Beta-Lapachone is associated with increases in Sirt1 expression, CREB phosphorylation and PGC-1 alpha deacetylation

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.