NAMPT protects against 6-hydroxydopamine-induced neurotoxicity in PC12 cells through modulating SIRT1 activity

Parkinson's disease (PD) is the second most common progressive neurodegenerative movement disorder. Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in the nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway in mammals, is a substrate for NAD+-dependent enzymes, such as sirtuin 1 (SIRT1), and contributes to cell fate decisions. However, the role of NAMPT in PD has remained to be fully elucidated. In the present study, PC12 cells were treated with the neurotoxin 6-hydroxydopamine (6-OHDA) to establish an in vitro model of PD, following which an obvious inhibitory effect on the levels of NAMPT and NAD+ as well as the NAD+/NADH ratio was detected. In addition, pre-incubation with FK866, a highly specific NAMPT inhibitor, enhanced the inhibitory effects of 6-OHDA on the viability of PC12, while pre-incubation with nicotinamide mononucleotide (NMN), am enzymatic product of NAMPT, had the opposite effect. Furthermore, it was revealed that NMN markedly attenuated 6-OHDA-induced decreases in superoxide dismutase activity and glutathione levels, as well as 6-OHDA-induced increases in malondialdehyde and lactate dehydrogenase in PC12 cells. Furthermore, 6-OHDA significantly reduced SIRT1 activity in PC12 cells, which was inhibited by NMN. The pharmacological activator resveratrol also significantly inhibited 6-OHDA-mediated decreases in PC12 cell viability while reversing 6-OHDA-induced decreases in SIRT1 levels. The results of the present study suggested that NMT protected against 6-OHDA-induced decreases in PC12 cell viability, and that SIRT1 activation had a role in this process. Treatment with NMN to activate SIRT1 may represent a novel therapeutic strategy for treating PD.