Hydrogen sulfide alleviates the anxiety-like and depressive-like behaviors of type 1 diabetic mice via inhibiting inflammation and ferroptosis

Studies reported that sodium hydrosulfide (NaHS) can remit the depressive-like and anxiety-like behaviors induced by type 1 diabetes mellitus (T1DM). However, the mechanism is still unclear. In this study, we aimed to investigate the mechanism of NaHS on T1DM. Mice were randomly divided into four groups, including the control group (CON group), DM group, DM + 5.6 mg/kg NaHS group, and CON + 5.6 mg/kg NaHS group. Data showed that NaHS did attenuate the depressive-like and anxiety-like behaviors by OFT, EPM test, FST, and TST. Results suggest that NaHS markedly alleviated the ferroptosis in the prefrontal cortex (PFC) of diabetic mice by reducing iron deposition and oxidative stress, increasing the expression of GPX4 and SLC7A11. Moreover, NaHS could dampen the activation of microglias and the release of pro-inflammatory cytokines, enhance the protein expression of sirtuin 6 (Sirt6) and the interaction between Sirt6 and the acetylation of histoneH3 lysine9 (H3K9ac), and decrease the protein expressions of the Notch1 receptor and H3K9ac. In vitro experiment, NaHS ameliorated the ferroptosis via increasing the protein expressions of SLC7A11, glutathione peroxidase 4 (GPX4), and cystathionine beta-synthase (CBS), reducing the pro-inflammatory cytokines, decreasing the levels of Fe2+, MDA, ROS, and lipid ROS. In conclusion, our results suggested that NaHS did alleviate anxiety-like and depressive-like behaviors. It can inhibit inflammation via modulating Sirt6 and was able to decrease the ferroptosis in the PFC of type 1 diabetic mice and the BV2 cells.