Hydrogen Sulfide Improves Chronic Restrain Stress-induced Hippocampal Damage And Cognitive Impairment By Upregulating Adiponectin

[Background and Objective]Chronic Restraint Stress?CRS? can lead to the hippocampal damage, including higher levels of oxidative stress, apoptosis, and dysfunction of synapse formation.Hydrogen sulfide?H₂S?, the third gas signaling molecule after CO and NO, can protect hippocampal neuron and improve the learning and memory function. This study explored whether H₂Scan improve CRS-caused cognitive impairment.Adiponectin?Acrp 30? can protect hippocampus against oxidative stress and apoptosis and prevent cognitive impairment. In the present work, we investigated whether adiponectin mediates the improving effects of H₂S on CRS-induced hippocampal damage and cognition impairment.[Methods]We builded the CRS model to observe the different effects of Na HS in SD rats. SD rats was treated with Na HS?100 ?mol/kg? by intraperitoneal injection in 8:00 am. After 30 min, SD rats were restrained for 6 hours. The cognitive functions were evaluated by Y-maze test,novel recognition test?NORT?, and Morris water maze?MWM? test. The levels of malondialdehyde?MDA?, glutathione?GSH? in the hippocampus were determined by enzyme-linked immunosorbent assay?ELISA?. The activity of superoxide dismutase?SOD? in the hippocampus was assayed by NBT assay. Western blotting was used to evaluate the protein expression of Acrp30 and synapsin 1?SYN-1?.Immunofluorescence technique determined the expression of synapsin 1. Tunel staining showed the apoptosis in hippocampal cells. Hematein Eosin staining showed the changes of hippocampus cellular structure.[Results]1.H₂S improves CRS-caused cognitive impairmentThe SD rats were treated with CRS 4 weeks. We use Y-maze, the novel object recognition test, and the Morris water maze?MWM? to test the learning and memory and cognitive function. The data from Y-maze test showed that Na HS?100?mol/kg× 28 d, ip?increased the alternation performance in CRS rats; The results from the novel object recognition test indicated that Na HS?100?mol/kg× 28 d, ip? improves the recognition index which was reduced by CRS.The results from the 5thday of acquisition phase in MWM test showed that the latency period of CRS rats was prolonged and their swimming route were more tortuous and complex. Treatment with Na HS?100?mol/kg× 28 d, ip? could reduce the CRS-induced delay of latency period.The spatial search experiment in MWM showed that the times of rats across platform, the time spend in target quadrant, and the proportionality of swimming time in mid-ring were reduced in the CRS-treated rats. Na HS?100?mol/kg× 28 d, ip? attenuated CRS-caused reductions in the times of rat across platform, the time spend in target quadrant, and the proportionality of swimming time in mid-ring.Above these results indicated that H₂S have antagonistic effects on CRS-induced cognitive impairment.2.H₂S improves CRS-caused hippocampal damageSD rats were treated with CRS for 4 weeks. The content of MDA was increased, GSH and SOD were decreased in CRS rats. Na HS?100?mol/kg×28d, ip? reversed these effects which induced by CRS; Western blotting andimmunofluorescence technique showed that the level of SNY 1 was reduced in CRS rats. The treatment with Na HS?100?mol/kg×28d, ip? increased the level of SNY 1 in CRS rats.HE staining showed that the hippocampal neuronal cells were decreased, arranged at random and loose, some nucleus were pycnosis in CRS rats.Na HS?100?mol/kg×28d, ip? can effectively antagonize the damage by CRS. Tunel staining showed that the apoptosis of hippocampal neuronal cells was raised in CRS rats, while Na HS?100?mol/kg×28d, ip? could reduce the apoptosis of hippocampal neuronal cells in CRS rats.All the results mentioned above indicated that H₂S prevent hippocampal damage from chronic restrained stress.3.H₂S upregulated the level of Acrp 30 in hippocampus of CRS rats.The level of Acrp 30 in hippocampus was evaluated by western blotting. The results demonstrated that Na HS?100?mol/kg×28d, ip? reversed CRS-caused down-regulation of Acrp 30.4. Acrp 30 mediates the antagonistic effect of H₂S on CRS-caused cognitive impairmentIn order to inhibited the activity of Acrp 30 in brain, rats were cotreated with Na HS?100?mol/kg/d, ip? and CRS?6h/d? for 28 d, and intracerebroventricularly injected with anti-acrp30?1 ?g/d? during the last 7 d.We used Y-maze, the novel object recognition test?NORT?, and the Morris water maze?MWM? to test the learning and memory and cognitive function of rats. The data from Y-maze test showed thatanti-acrp30?1 ?g/d, for 7 d? reversed the protective effects of Na HS?100?mol/kg× 28 d, ip? on CRS-decreased in rat alternative performance. The results from the novel object recognition test indicated that anti-acrp30?1 ?g/d, for 7 d? reversed the role of Na HS?100?mol/kg×28d, ip? in improving novel object recognition index.The results from the 5thday of acquisition phase in MWM test showed that anti-acrp30?1 ? g/d, for 7 d? could reverse the protection of Na HS?100?mol/kg× 28 d, ip? against CRS-induced delay of latency period. The spatial search experiment showed that anti-acrp30?1 ?g/d, for 7 d? reversed the protections of Na HS?100?mol/kg× 28 d, ip? against CRS-decreased in the times of rats across platform, the time spended in target quadrant, and the proportionality of swimming time in mid-ring.Above these results demonstrated that Acrp 30 mediated the antagonistic effect of H₂S on CRS-caused cognitive impairment.5. Acrp 30 mediates the antagonistic effect of H₂S on CRS-caused hippocampal damageInhibiting Acrp 30 reversed the protection of H₂S against CRS-caused oxidative stress and down-regulation of SYN 1. HE staining showed that blocking Acrp 30 reversed the antagonistic effect of H₂S on CRS-caused hippocampal neuronal cells damage. Tunel staining showed that anti-acrp30?1?g/d, for 7 d? abolished H₂S-elicited the decline in hippocampal neuronal cells apoptosis of CRS rats.All the results demonstrated Acrp 30 mediated the antagonistic effect of H₂S on CRS-caused hippocampal damage.[Conclusion]1. H₂S improves CRS-induced hippocampal damage and cognitive impairment.2. Adiponectin mediates the protective effects of hydrogen sulfide on CRS-induced hippocampal damage and cognitive impairment.