The protective effects of Agomelatine against Aβ1-42 oligomers-induced cellular senescence mediated by SIRT6 and Agomelatine's potential in AD treatment

Alzheimer's disease (AD) is a vicious degenerative disease commonly observed in the elderly population, and the deposition of Amyloid beta (A beta) is regarded as the principal pathological inducement of AD. Severe oxidative stress, inflammatory reactions, and cell senescence in neurons can be induced by A beta 1-42 oligomers, which further contribute to the damage on neurons. Agomelatine is an antidepressant that is recently claimed to have promising anti-oxidative stress and anti-inflammatory effects. The present study aims to explore the potential therapeutic function of Agomelatine on AD and the possible mechanism. A beta 1-42 oligomers were used to induce an in vitro injury model in SH-SY5Y neuronal cells. First, we found that exposure to A beta 1-42 oligomers significantly exacerbated oxidative stress by increasing hydrogen peroxide production and reducing glutathione peroxidase (GPx), which were partially rescued by Agomelatine. Also, Agomelatine attenuated A beta 1-42 oligomers-induced inflammatory response by decreasing the expression of TNF-alpha and IL-1 beta. Notably, Agomelatine improved cellular senescence by reducing senescence-associated beta-galactosidase (SA-beta-Gal) staining and mitigating A beta 1-42 oligomers-induced reduction of telomerase activity. In addition, the upregulated p16(INK4A) and p21(CIP1) and the suppressed expression of SIRT6 in Af31-42 oligomers-treated cells were reversed by Agomelatine. Lastly, after the knockdown of SIRT6, the protective effect of Agomelatine against A beta 1-42 oligomers-induced cellular senescence was significantly eliminated. In conclusion, our data indicated that Agomelatine ameliorated A beta 1-42 oligomers-induced cellular senescence mediated by SIRT6, and thus, Agomelatine could be effective in treating AD.