Hydrogen sulfide attenuates postoperative cognitive dysfunction through promoting the pathway of Warburg effect-synaptic plasticity in hippocampus.

Postoperative cognitive dysfunction (POCD) is deemed to a severe surgical complication without effective treatment. Previous work has confirmed the important modulatory role of hydrogen sulfide (H2S) in cognitive function. This study was proposed to explore whether H2S relieves POCD and the possible mechanisms. We demonstrated that NaHS (a donor of H2S) reversed the inhibited endogenous H2S generation in the hippocampus of postoperative rats. NaHS attenuated the cognitive impairment of postoperative rats in the Y-maze, Novel object recognition, and Morris water maze tests. NaHS enhanced the expressions of synaptic plasticity-related proteins, synapsin-1 and PSD-95, increased the synaptic density, and decreased the destruction of synaptic structures in the hippocampus of postoperative rats. Moreover, NaHS promoted Warburg effect in the hippocampus of postoperative rats, as reflected by increases in the expressions of hexokinase 2, pyruvate kinase M2, lactate dehydrogenase A, and pyruvate dehydrogenase kinase 1, an enhancement in the content of lactate, and a reduction in the expression of pyruvate dehydrogenase. The inhibitor of Warburg effect, 2-Deoxy-D-glucose (2-DG), not only reversed NaHS-enhanced Warburg effect in the hippocampus of postoperative rats, but also significantly abolished NaHS-exerted protective effect on cognitive function. Furthermore, 2-DG reversed NaHS-exerted enhancement in the expressions of synapsin-1 and PSD-95, increase in the synaptic density, and decrease in the destruction of synaptic structures in the hippocampus of postoperative rats. Collectively, these results indicate that H2S alleviates POCD through enhancing hippocampal Warburg effect, which subsequently improves synaptic plasticity in the hippocampus.

BDNF-TrkB pathway mediates antidepressant-like roles of H2 S in diabetic rats via promoting hippocampal autophagy.

Hydrogen sulfide (H2 S) plays antidepressant-like roles in diabetic rats. However, the underlying mechanisms remain unclear. Brain-derived neurotropic factor (BDNF), a neurotrophic factor, plays important regulatory roles in depression by its high-affinity tropomysin-related kinase B (TrkB) receptor. Autophagy also is implicated in modulation of depression. Previous work confirmed the modulatory roles of H2 S in BDNF protein expression and autophagy. Thus, in this study, we explored whether the BDNF-TrkB pathway mediates the antidepressant-like effects of H2 S in diabetic rats and whether this process is achieved via promoting hippocampal autophagy. We demonstrated that H2 S upregulated the expressions of BDNF and p-TrkB proteins in the hippocampus of streptozotocin (STZ)-induced diabetic rats. K252a (an inhibitor of BDNF-TrkB pathway) reversed the antidepressant-like roles of H2 S, as evidenced by the tail suspension, forced swimming, novelty suppressed feeding, and elevated plus-maze tests. Furthermore, K252a abolished H2 S-promoted hippocampal autophagy in diabetic rats, as evidenced by a decrease in the number of autolysosome, downregulation of Beclin-1 (a regulator of autophagy in the early stage of the formation of autophagosomal membranes and its level is positively correlated with autophagic activity) expression, and upregulation of P62 (a substrate of autophagic degradation and its level is inversely correlated with autophagic activity) expression, in the hippocampus of rats co-treated with NaHS and STZ. Taken together, these data indicated that the BDNF-TrkB pathway mediates the antidepressant-like roles of H2 S in diabetic rats by enhancing hippocampal autophagy.