Alpha-Lipoic Acid Attenuates MPTP/MPP+-Induced Neurotoxicity: Roles of SIRT1-Dependent PGC-1α Signaling Pathways

Abstract

Accumulated oxidative damage plays key roles in the pathogenesis of Parkinson's disease (PD). Silent mating type information regulation 2 homolog 1 (SIRT1), a class III histone deacetylase, can directly activate peroxisome proliferator-activated receptor-c coactivator-1α (PGC-1α) and attenuate oxidative stress. Alpha-lipoic acid (ALA) is a natural antioxidant that has been demonstrated to protect PC12 cells against 1-methyl-4-phenylpyridinium (MPP⁺). However, the underlying mechanisms related to changes in cell signaling cascades are not fully understood. In the present study, the neuroprotective effect of ALA and the potential role of ALA in the SIRT1 pathway was investigated in vitro and in a mouse model of PD. A Cell Counting Kit-8 (CCK-8) assay was performed to detect the SY5Y-SH cell viability. Immunohistochemistry, quantitative real-time polymerase chain reaction and western blot assays were used to evaluate the expression of tyrosine hydroxylase (TH), SIRT1, and PGC-1α in vivo and in vitro. Intracellular reactive oxygen species (ROS) production and tissue SOD and MDA were detected by the corresponding assay kits. The results showed that ALA notably prevented oxidative stress and neurotoxicity in vivo and in vitro against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)/MPP⁺. Furthermore, ALA significantly increased the expression of SIRT1 and PGC-1α in vivo and in vitro in MPTP/MPP⁺-induced models, which was reversed by the SIRT1 inhibitor EX527. These results suggested that ALA prevented oxidative stress and that neurotoxicity was involved in the upregulation of SIRT1 and PGC-1α in PD mice.

Keywords: Alpha-lipoic acid; Oxidative stress; Parkinson’s disease; Peroxisome proliferator-activated receptor-c coactivator-1α; Silent mating-type information regulation 2 homolog 1.