Hydrogen Sulfide Inhibits High Glucose-Induced Neuronal Senescence by Improving Autophagic Flux via Up-regulation of SIRT1

Hyperglycemia, a key characteristic and risk factor for diabetes mellitus (DM), causes neuronal senescence. Hydrogen sulfide (H(2)S) is a novel neuroprotectant. The present work was to investigate the potential effect of H(2)S on hyperglycemia-induced neuronal senescence and the underlying mechanisms. We found that NaHS, a donor of H(2)S, inhibited high glucose (HG)-induced cellular senescence in HT22 cells (an immortalized mouse hippocampal cell line), as evidenced by a decrease in the number of senescence associated-β-galactosidase (SA-β-gal) positive cells, increase in the growth of cells, and down-regulations of senescence mark proteins, p16(INK4a) and p21(CIP1). NaHS improved the autophagic flux, which is judged by a decrease in the amount of intracellular autophagosome as well as up-regulations of LC3II/I and P62 in HG-exposed HT22 cells. Furthermore, blocked autophagic flux by chloroquine (CQ) significantly abolished NaHS-exerted improvement in the autophagic flux and suppression in the cellular senescence of GH-exposed HT22 cells, which indicated that H(2)S antagonizes HG-induced neuronal senescence by promoting autophagic flux. We also found that NaHS up-regulated the expression of silent mating type information regulation 2 homolog 1 (SIRT1), an important anti-aging protein, in HG-exposed HT22 cells. Furthermore, inhibition of SIRT1 by sirtinol reversed the protection of H(2)S against HG-induced autophagic flux blockade and cellular senescence in HT22 cells. These data indicated that H(2)S protects HT22 cells against HG-induced neuronal senescence by improving autophagic flux via up-regulation of SIRT1, suggesting H(2)S as a potential treatment strategy for hyperglycemia-induced neuronal senescence and neurotoxicity.