Exogenous hydrogen sulfide ameliorates diabetes-associated cognitive dysfunction by regulating the nrf-2/HO-1 axis and the NLRP3 inflammasome pathway in diabetic rats

Diabetes-associated cognitive dysfunction (DACD) is a complication of diabetes mellitus that leads to an increased risk of cognitive impairment and dementia. However, the molecular mechanism underlying DACD has not been elucidated, and a promising therapy for this disease remains to be established. Hydrogen sulfide (H2S), a significant antioxidative and anti-inflammatory gasotransmitter, has emerged as a neuroprotective agent. In this study, we investigated the protective effects of H2S on DACD in a streptozotocin (STZ)-induced diabetic rat model. We applied the Morris water maze to evaluate spatial learning and memory abilities. We used Western blotting and immunohistochemical staining to investigate the expression of the Nrf-2/HO-1 axis and the NLRP3 inflammasome. After NaHS (H2S donor) administration, diabetic rats exhibited improved spatial learning and memory retrieval abilities in the Morris water maze. In STZ-induced diabetic rats, the protein expression levels of the Nrf-2/HO-1 axis, the NLRP3 inflammasome and subsequent inflammatory cytokines in the hippocampal region were elevated compared to those in control rats. Exogenous H2S triggered Nrf-2/HO-1 antioxidant activity and inhibited NLRP3 inflammasome activation and proinflammatory cytokine expression. These findings suggested that exogenous H2S has neuroprotective effects by modulating the Nrf-2/HO-1 axis and the NLRP3 inflammasome pathway, which were found to be associated with DACD. H2S treatment may be a promising therapeutic strategy for preventing the progression of tissue damage caused by DACD.