Effects And Mechanism Of Gaseous Signal Molecule Hydrogen Sulfide On The Depressive-like Behavior Induced By Chronic Unpredictable Stress Of Rats

Part I Effects of hydrogen sulfide on behavioral deficits caused by chronic unpredictable mild stress in ratsAim:As an endogenous gas molecule in mammals, hydrogen sulfide (H2S) exerts a host of biological effects in central nervous system. Numerous studies have shown a close link between the imbalance of endogenous H2S in brain and the pathophysiology of Alzheimer’s disease (AD), Parkinson’s disease (PD) and stroke. However, little is known about whether depression is associated with the changes of H2S content in brain and whether exogenous regulation of H2S content has antidepressant effect. We postulated that H2S might participate in the formation of neurobehavioral adaptations during depression.Methods:Application of chronic unpredictable mild stress (CUMS) paradigm for research. GC-MS was used to analyze the content of endogenous H2S in the hippocampus of rats; Behavioral experiments including sucrose preference test, novelty-suppressed feeding test, and forced swimming text were adopted to investigate animals’ response to the H2S treatment. The effects of H2S on the changes of dendritic spines density were observed by Golgi staining. To detect the effect of H2S on HPA axis, we analyzed the level of serum corticosterone by using ELISA kit.Results:We found that the level of endogenous H2S was significant lower in hippocampus of rats submitted to CUMS. Both NaHS injection and inhaled H2S elevated the decreased level of H2S. Moreover, NaHS (11.2mg/kg) significantly reduced the immobility in forced swimming test within30min and this effect could last for1week, which was better than MK-801or fluoxetine. H2S reversed the decreased sucrose preference, the increased latency to feed and immobility of rat, indicating that H2S produces rapid antidepressant responses in CUMS paradigm. In addition, H2S increased the dendritic spine density in hippocampus, but had no effect on the level of serum corticosterone of rats which exposed to CUMS procedure.Conclusion:Chronic unpredictable mild stress caused the decrease in endogenous H2S in the hippocampus of rats. However, administration of exogenous H2S could reverse the behavioral deficits caused by acute or chronic stress exposure. These results suggest that upregulation of H2S level in hippocampus could be a new strategy for depression treatment. Part Ⅱ Mechanisms of antidepressant effect of hydrogen sulfide in rats submitted to chronic unpredictable stressAim:In recent years, the rapid therapeutic response of ketamine in treatment-resistant patients is the biggest breakthrough in depression research. In addition, ketamine has served as a useful tool to provide a compelling rationale for studying the mechanism of fast-onset antidepressants. Otherwise, a growing body of literature suggests that there is a high correlation between the activation of mTOR signaling pathway and the rapid antidepressant effects. But little is known about the rapid-onset antidepressant-like effect of H2S on the mTOR-related signaling pathway. In this study, we will explore the possible molecular mechanism to uncover novel strategies of H2S in depression treatment.Methods:Western blotting was used to investigate protein expressions in the mTOR and its downstream signaling pathways of CUMS rats after H2S treatment. Application of pharmacological blockade and lentiviral-shRNA, combined with behavioral test, were used to identify the antidepressant effect of H2S and to explore the potential mechanism.Results:Using Western blot, we found that H2S rapidly activated the mTORCl signaling and its downstream pathway of P70S6k in hippocampus of rats. Rapamycin and raptor shRNA blocked the expression of mTORCl and abolished the antidepressant effect of H2S. Furthermore, H2S promoted the synaptic protein synthesis, including PSD95and synaptophysin. H2S also increased total GluR1and GluRl tyrosine phosphorylation of glutamatergic AMPA receptor.Conclusion:The antidepressant effect of hydrogen sulfide was predominantly mediated through activating the mTORCl signaling pathway, promoting the synthesis of synaptic proteins, including PSD95and Synaptophysin. Moreover, H2S upregulated the TrkB receptor and further increased total GluR1expression and GluR1tyrosine phosphorylation of glutamatergic AMPA receptor.