Hydrogen Sulfide Antagonizes Chronic Restraint Stress-Induced Depressive-Like Behaviors Of Rats By Up-Regulation Of SIRT1

[Background and Objective] Chronic restraint stress（CRS） can induce Depression-like behaviors in rodents. Hydrogen sulfide（H2S）, a novel gasotransmitter, can produce a neuroprotective effect. Our previous work showed that H₂S significantly attenuated depressive-like behaviors of rats. But, Whether H₂S can antagonize CRS-induced depression-like behaviors in rats and what is its mechanism of action.Silence signal regulating factor 1（SIRT1）, a kind of histone deacetylase depends on the nicotinamide adenine dinucleotide（NAD+）, has the antidepressant effect. Accordingly, we will investigate whether the mechanism of H₂S antagonizes CRS-induced depressive-like behaviors in rats by up-regulation of SIRT1.In the present study, we established a CRS model to investigate the antagonistic effect of H₂S on depressive behavior of CRS rats and the expression of SIRT1, and to explore whether SIRT1 mediates this role of H₂S. [Methods] Male Sprague Dawley rats（200-240 g） were chronic bondage four weeks to establish a CRS model.Then, NaHS（30 or 100 μmol/kg） was injected intraperitoneally（ip, 4 w）.SD rats were treated with right-sidedness lateral ventricle pipe understereotaxic instrument. Sirtinol（10 nmol, icv, 1 w） was injected into the lateral ventricle of rats with micro-syringe. Expressions of SIRT1 in hippocampus of rats were measured by Western blot. To test the depressive behavior of rats, we used the forced swimming test（FST）, the tail suspension test（TST） and novelty suppressed feeding test（NSFT）.The locomotor activity was tested by open field test. [Results] 1. H₂S attenuates CRS-induced depressive-like behavior of rats. Cotreatment with CRS and NaHS（30 or 100 μmol/kg, ip） for 4 w. The results from forced swimming test showed that the immobility time of CRS-induced rats were significantly increased and the climbing time were significantly decreased, however NaHS（30 or 100 μmol/kg, ip, 4 w） significantly improved the depression behavior in the forced swimming test of rats.The data from tail suspension test indicated that the immobility time of CRS-induced rats were significantly increased, however NaHS（30 or 100μmol/kg, ip, 4 w） significantly decreased the immobility time of rats. The results from novelty suppressed feeding test demonstrated that the latency to feed of CRS-induced rats were significantly increased, while NaHS（30or 100 μmol/kg, ip, 4 w） significantly decreased the latency to feed of rats.These results demonstrated that H₂S attenuates CRS-induced depressive-like behavior of rats. 2. H₂S up-regulates the expressions of SIRT1 in the hippocampus of CRS-induced rats. The expression levels of SIRT1 in CRS-induced rats hippocampus were significantly decreased,while NaHS（100 μmol/kg, ip, 4 w） reversed the repressive effect of CRS on the expression levels of SIRT1 in rats hippocampus.These results suggested that H₂S up-regulated the expression of SIRT1 in the hippocampus of CRS-induced rats. 3. Inhibiting SIRT1 can reverse the protection of H₂S against CRS-induced depressive-like behavior of rats. CRS combined with NaHS（100 μmol/kg, ip） for 4 w and sirtinol（10 nmol, icv） for 1 w after 3 w-CRS. The results from FST showed that sirtinol（10 nmol） reversed the protective effect of H₂S on CRS-induced depressive-like behavior of rats. The data from TST indicated that sirtinol（10 nmol） reversed the protective effect of H₂S on the immobility time of CRS-induced rats. The results from NSFT demonstrated that sirtinol（10nmol） reversed the protective effect of H₂S on the latency to feed of CRS-induced rats. These results indicated that inhibited SIRT1 reversed the protection of H₂S against CRS-induced depressive-like behavior of rats. [Conclusion] 1. H₂S improves CRS-induced depressive-like behavior of rats. 2. SIRT1 mediated the protection of H₂S against CRS-induced depressive-like behavior of rats.