Hydrogen Sulfide Antagonizes CUMS-induced Endoplasmic Reticulum Stress In The Hippocampus Of Rats By Up-regulation Of SIRT1

[Background and Objective]Chronic stress can induce the damage of hippocampal neuron.Hydrogen sulfide (H2S), a novel gasotransmitter, can produce aneuroprotective effect. Our previous work showed that H2S significantlyattenuated chronic stress-induced damage in the hippocampus of rats;however, the underlying mechanisms have not yet been identified.Silence signal regulating factor1(SIRT1), a kind of histone deacetylasedepends on the nicotinamide adenine dinucleotide (NAD+), has theneuroprotective effect. Endoplasmic reticulum (ER) stress plays animportant role in the damage of neuron. Thus, we speculated that H2Sextenuates CUMS-induced damage in hippocampus by inhibition ofhippocampal ER stress through upregulating Sirt1expression.In the present study, we established a chronic unexpected mild stress(CUMS) model to investigate the antagonistic effect of H2S onCUMS-induced ER stress and to explore whether SIRT1mediates this roleof H2S.[Methods]Wistar rats were treated with right-sidedness lateral ventricle pipe understereotaxic instrument. Sirtinol (10nmol, icv,2w) was injected into the lateral ventricle of rats with micro-syringe. NaHS (30or100μmol/kg) wasinjected intraperitoneally (ip,2w). Expressions of GRP78, CHOP,Cleaved caspase-12and SIRT1in hippocampus of rats were measuredby Western blot.[Results]1. H2S reduces ER stress in the hippocampus of CUMS-treated rats.Compared with CUMS (4w) group, the expressions of the endoplasmicreticulum stress-related marker proteins (GRP78, CHOP and Cleavedcaspase-12) in the hippocampus of NaHS-treated rats [CUMS for4wand NaHS (30or100μmol/kg, ip) for2w after2w-CUMS] weresignificantly decreased. These results demonstrated that H2S attenuatesCUMS-induced hippocampal ER stress.2. H2S upregulates the expressions of SIRT1in the hippocampus ofCUMS–treated rats.CUMS (4w) significantly decreased the expression levels of SIRT1in ratshippocampus, while NaHS treatment (30or100μmol/kg, ip) reversedthe downregulation of SIRT1in the hippocampus of CUMS-treated rats,suggested that H2S upregulated the expression of SIRT1in thehippocampus of CUMS-treated rats.3. Inhibiting SIRT1can reverse the protection of H2S againstCUMS-induced hippocampal ER stress.Compared with NaHS treatment group [CUMS for4w and NaHS (30μmol/kg, ip) for2w after2w-CUMS], the expressions of ER stress-relatedmarker proteins (GRP78, CHOP and Cleaved caspase-12) significantlyincreased in the hippocampus of sirtinol-treated rats [CUMS for4w andcombined with NaHS (30μmol/kg, ip) and sirtinol (10nmol, icv) for2wafter2w-CUMS], which indicated that inhibited SIRT1reversed theprotection of H2S against CUMS-induced hippocampal ER stress.[Conclusion]1. H2S antagonised CUMS-induced damage in hippocampus by amelioration of hippocampal endoplasmic reticulum stress.2. SIRT1mediated the protection of H2S againsting CUMS-inducedhippocampal ER stress.