Hydrogen Sulfide Inhibits Formaldehyde-Induced Senescence in HT-22 Cells via Upregulation of Leptin Signaling

It has been previously demonstrated that hydrogen sulfide (H 2 S) prevents formaldehyde (FA)-induced neurotoxicity. However, the exact mechanisms underlying this protection remain to be fully elucidated. Neuronal senescence is involved in FA-induced neurotoxicity. Leptin signaling has anti-aging function. The present work was to investigate the protection of H 2 S against FA-induced neuronal senescence and the mediatory role of leptin signaling. FA-exposed HT-22 cells were used as the vitro model of FA-induced neuronal senescence. The senescence-associated β-galactosidase (SA-β-Gal) positive cell was detected by β-galactosidase staining. The expressions of P16 INK4a , P21 CIP1 , leptin, and lepRb (leptin receptor) were measured by western blot. The proliferation, viability, and apoptosis of cells were evaluated by Trypan blue exclusion assay, Cell Counting Kit-8 (CCK-8) assay, and Flow cytometry analysis, respectively. We found that H 2 S suppressed FA-induced senescence, as evidenced by the decrease in SA-β-Gal positive cells, the downregulations of P16 INK4a and P21 CIP1 , as well as decrease in cell growth arrest, in HT-22 cells. Also, H 2 S upregulated the expressions of leptin and lepRb in FA-exposed HT-22 cells. Furthermore, leptin tA (a specific inhibitor of the leptin) abolished the protective effects of H 2 S on FA-induced senescence and neurotoxicity (as evidenced by the increase in cell viability and the decrease in cell apoptosis) in HT-22 cells. These results indicated that H 2 S prevents FA-induced neuronal senescence via upregulation of leptin signaling. Our findings offer a novel insight into the mechanisms underlying the protection of H 2 S against FA-induced neurotoxicity. Graphical Abstract FA upregulates the expressions of P16 INK4a and P21 CIP1 via inhibiting leptin signaling, which in turn induces senescence in HT-22 cells; H 2 S downregulates the expressions of P16 INK4a and P21 CIP1 via reversing FA-downregulated leptin signaling, which in turn prevents FA-induced senescence in HT-22 cells.