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SIRT1 Mediates H2S-Ameliorated Diabetes-Associated Cognitive Dysfunction in Rats: Possible Involvement of Inhibiting Hippocampal Endoplasmic Reticulum Stress and Synaptic Dysfunction

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Abstract

Diabetes-associated cognitive dysfunction (DACD) characterized by hippocampal injury increases the risk of major cerebrovascular events and death. Endoplasmic reticulum (ER) stress and synaptic dysfunction play vital roles in the pathological process. At present, no specific treatment exists for the prevention and/or the therapy of DACD. We have recently reported that hydrogen sulfide (H2S) exhibits therapeutic potential for DACD, but the underlying mechanism has not been fully elucidated. Silent information regulator 1 (SIRT1) has been shown to play a role in regulating the progression of diabetes and is also indispensable for memory formation and cognitive performance. Hence, the present study was performed to explore whether SIRT1 mediates the protective effect of H2S on streptozotocin (STZ)-induced cognitive deficits, an in vivo rat model of DACD, via inhibiting hippocampal ER stress and synaptic dysfunction. The results showed that administration of NaHS (an exogenous H2S donor) increased the expression of SIRT1 in the hippocampus of STZ-induced diabetic rats. Then, results proved that sirtinol, a special blocker of SIRT1, abrogated the inhibition of NaHS on STZ-induced cognitive deficits, as appraised by Morris water maze test, Y-maze test, and Novel object recognition behavioral test. In addition, administration of NaHS eliminated STZ-induced ER stress as evidenced by the decreases in the expressions of ER stress-related proteins including glucose-regulated protein 78, C/EBP homologous protein, and cleaved caspase-12 in the hippocampus, while these effects of NaHS were also reverted by sirtinol. Furthermore, the NaHS-induced up-regulation of hippocampal synapse-related protein (synapsin-1, SYN1) expression in STZ-induced diabetic rats was also abolished by sirtinol. Taken together, these results demonstrated that SIRT1 mediates the protection of H2S against cognitive dysfunction in STZ-diabetic rats partly via inhibiting hippocampal ER stress and synaptic dysfunction.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81671057) and the Hunan Provincial Natural Science Foundation of China (2019JJ50546, 2019JJ80101).

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  1. Juan He and Zhuo Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Affiliated Nanhua Hospital, University of South China, No. 336, Dongfeng South Road, Hengyang, 421001, Hunan, People’s Republic of China

    Juan He, Zhuo Chen, Lin Wu, Su-Mei Liu, Yong-Jun Chen, Wei Zou & Ping Zhang

  2. Institute of Neuroscience, Hengyang Medical College, University of South China, Hengyang, 421001, Hunan, People’s Republic of China

    Juan He, Zhuo Chen, Xuan Kang, Lin Wu, Su-Mei Liu, Hai-Jun Wei, Yong-Jun Chen, Wei Zou, Chun-Yan Wang & Ping Zhang

  3. Department of Neurology, Yiyang Center Hospital, Yiyang, 413000, Hunan, People’s Republic of China

    Zhuo Chen

  4. Department of Neurology, the First Affiliated Hospital, University of South China, No. 69 Chuanshan Road, Hengyang, 421001, Hunan, People’s Republic of China

    Xuan Kang, Jia-Mei Jiang & Hai-Jun Wei

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  1. Juan He
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He, J., Chen, Z., Kang, X. et al. SIRT1 Mediates H2S-Ameliorated Diabetes-Associated Cognitive Dysfunction in Rats: Possible Involvement of Inhibiting Hippocampal Endoplasmic Reticulum Stress and Synaptic Dysfunction. Neurochem Res 46, 611–623 (2021). https://doi.org/10.1007/s11064-020-03196-8

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