Comparative Mitochondrial-Based Protective Effects of Resveratrol and Nicotinamide in Huntington’s Disease Models

Luana Naia, Tatiana R. Rosenstock, Ana M. Oliveira, Sofia I. Oliveira-Sousa, Gladys L. Caldeira, Catarina Carmo, Mário N. Laço, Michael R. Hayden, Catarina R. Oliveira, A. Cristina Rego; Mol Neurobiol (2016). doi:10.1007/s12035-016-0048-3

In this study, we tested the influence of resveratrol (RESV, a SIRT1 activator) versus nicotinamide (NAM, a SIRT1 inhibitor) in counteracting mitochondrial dysfunction in HD models. Further studies revealed decreased PGC-1α and TFAM protein levels, linked to mitochondrial DNA loss in HD lymphoblasts. Remarkably, RESV completely restored these parameters, while NAM increased NAD+ levels, providing a positive add on mitochondrial function in in vitro HD models. In general, RESV decreased while NAM increased H3 acetylation at lysine 9. In agreement with in vitro data, continuous RESV treatment for 28 days significantly improved motor coordination and learning and enhanced expression of mitochondrial-encoded electron transport chain genes in YAC128 mice. In contrast, high concentrations of NAM blocked mitochondrial-related transcription, worsening motor phenotype. Overall, data indicate that activation of deacetylase activity by RESV improved gene transcription associated to mitochondrial function in HD, which may partially control HD-related motor disturbances.

 Comparative Mitochondrial-Based Protective Effects of Resveratrol and Nicotinamide in Huntington’s Disease Models