| Backgroud and ObjectiveSleep deprivation(SD) has shown negative effects on cognitive function in humans. How to prevent SD-induced cognitive impairment is a focus in the field of neuroscience. The hippocampus, a key part of the limbic system, plays a central role in regulation of learning and memory, while hippocampal damage is an important factor for cognitive impairment. Silent information regulator 1(Sirt1), a member of sirtuins family highly expressed in hippocampus, regulates cognitive function and attenuates hippocampal damage. Hydrogen sulfide(H2S), a neuronal protective factor, not only regulates learning and memory, but also increases the expression of Sirt1 in hippocampus. In present study, we investigated whether H2 S improves SD-induced cognitive impairment in rats and the underling mechanisms. MethodsAdult male Wistar rats were exposed to sleep deprivation(SD) for 72 h using the modified multiple platform method(MMPM). The cognitive function was evaluated by Y-maze test, novel object recognition test(NORT) and Morris water maze(MWM) test. The neuronal arrangement and quantity in hippocampus was observed under microscope using Hematoxylin-Eosin(HE) staining. The neuronal apoptosis in hippocampus was observed under microscope using Terminal-deoxynucleotidyl transferase-mediated dUTP nick-end labeling(Tunel) staining. The level of H2 S in the hippocampus was measured by N, N-dimethyl-p-phenylenediamine sulphate(NNDPD) method. The expressions of Cystathionine-bata-synthase(CBS), 3-mercaptopyruvate sulphurtransferase(3-MST), Sirt1, Bcl-2, and Bax in hippocampus were detected by Western blot. The activity of hippocampal caspase-3 was analyzed by Enzyme-linked immuno sorbent assay(Elisa). Results1. SD induced cognitive impairment in rats. Exposure to SD for 72 h decreased the alternation performance in Y-maze test and the new object recognition index of rats in NORT, increased the escape latency of rats in the fifth-day of acquisition phase of MWM test, reduced the across times and spending time of rats in the platform quadrant as well as the swimming time of rats in mid-ring in probe trial of MWM test. These results indicated that SD induced cognitive impairment in rats.2. SD induced hippocampal damage in rats. 72 h-SD induced the decrease in the number and disorder distribution of neurons and the incresae in the amount of apoptotic hippocamal neuron in CA3 area, the enhancment in the activity of Caspase-3, the downregulation of Bcl-2 expression, and the upregulation of Bax expression in hippocampus of rats. These results indicated that SD induced the damage of hippocampus in rats.3. SD decreased the endogenous production of H2 S in the hippocampus of rats. 72 h-SD significantly decreased the expression of CBS, 3-MST and the generation of H2 S in the hippocampus of rats, which indicated that SD inhibits the generation of hippocampal H2 S.4. H2 S improved cognitive impairment in sleep deprivation(SD) rats. Rats were pretreated with NaHS(30 and 100 ?mol/kg/d, ip) for 7 d, and then cotreated with SD for 72 h. NaHS(30 and 100 ?mol/kg) increased the alternation performance of SD rats in Y-maze test and the new object recognition index of SD rats in NORT, decreased the escape latency of SD rats in the fifth-day of acquisition phase of MWM test, incrased the across times and spending time in the platform quadrant, and elevated the swimming time of SD rats in mid-ring in probe trial of MWM test. These results indicated that H2 S improves cognitive impairment in SD rats.5. H2 S alleviated the hippocampal damage in sleep deprivation(SD) rats. Rats were pretreated with NaHS(30 and 100 ?mol/kg/d, ip) for 7 d, and then cotreated with SD for 72 h. NaHS(30 and 100 ?mol/kg) significantly improved the number and arrangement of neuron and decresaed the amount of apoptotic neuron in CA3 areas of SD rats, reduced the activity of Caspase-3, upregulated Bcl-2 expression, and downregulated Bax expression in hippocampus of SD rats. These results indicated that H2 S prevents the hippocampal damage in SD rats.6. H2 S upregulated the expression of hippocampal Sirt1 in sleep deprivation(SD) rats. NaHS(30 and 100 ?mol/kg) markedly restored 72 h-SD-induced downregulation of Sirt1 proteins in hippocampus of rats.7. Sirtinol reverses the ability of H2 S to improve cognitive impairment in sleep deprivation(SD) rats. Rats were pretreated with NaHS(30 and 100 ?mol/kg/d, ip) for 7 d, and then cotreated with SD for 72 h and Sirtinol(10 nmol/d, icv) for 3 d. Sirtinol(10 nmol) attenuated NaHS(30 and 100 ?mol/kg)-induced increase in the alternation performance of SD rats in Y-maze test and the new object recognition index of SD rats in NORT, decrease in the escape latency of SD rats in the fifth-day of acquisition phase of MWM test, increase in the across times and spending time in the platform quadrant, and elevation in swimming time of SD rats in mid-ring in probe trial of MWM test. The results indicated that Sirt1 mediates the improving function of H2 S in SD-induced cognitive impairment.8. Sirtinol reverses the ability of H2 S to improve hippocampal damage in sleep deprivation(SD) rats. Sirtinol(10 nmol) reverse Na HS(30 and 100 ?mol/kg)-induced improvment in the number and arrangement of neuron in CA3 areas, decrease in the amount of apoptotic neuron in CA3 areas, enhancment in the activity of Caspase-3, upregulation of Bcl-2 expression, and downregulation of Bax expression in hippocampus of SD rats. These results indicated that Sirt1 mediates the antagonistic effect of H2 S on SD-induced hippocampal damage. Conclusion1. H2 S improves SD-induced cognitive impairment and hippocampal damage in rats;2. H2 S improves cognitive impairment in sleep deprivation(SD) rats by upregulation of hippocampal Sirt1, which is involved in alleviating hippocampal damage in rats. |
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