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

ABSTRACT

Huntington's disease (HD) is one of the most devastating genetic neurodegenerative disorders with no effective medical therapy. ß-Lapachone (ßL) 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-1α) which is associated with mitochondrial respiration and biogenesis. To examine the effectiveness of ßL on HD, ßL 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-1α deacetylation were examined. Western blot results showed that Sirt1 and p-CREB levels were significantly increased in the brains of ßL-treated R6/2 mice. An increase in deacetylation of PGC-1α, which is thought to increase its activity, was observed by oral administration of ßL. In an in vitro HD model, ßL treatment resulted in an attenuation of MitoSOX red fluorescence intensity, indicating an amelioration of mitochondrial reactive oxygen species by ßL. Furthermore, improvements in the rota-rod performance and clasping score were observed in R6/2 HD mice after oral administration of ßL compared to that of vehicle control-treated mice. Taken together, our data show that ßL 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 ßL.