Department of Neurology, Affiliated Nanhua Hospital, University of South China, No. 336, Dongfeng South Road, Hengyang, 421001, Hunan, People's Republic of China.
Institute of Neuroscience, Hengyang Medical College, University of South China, Hengyang, 421001, Hunan, People's Republic of China.
Neurochem Res. 2021 Mar;46(3):611-623. doi: 10.1007/s11064-020-03196-8. Epub 2021 Feb 3.
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 (HS) 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 HS 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 HS 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 HS against cognitive dysfunction in STZ-diabetic rats partly via inhibiting hippocampal ER stress and synaptic dysfunction.
糖尿病相关认知功能障碍（DACD）的特征是海马损伤，增加了发生主要脑血管事件和死亡的风险。内质网（ER）应激和突触功能障碍在病理过程中起着至关重要的作用。目前，尚无针对 DACD 的预防和/或治疗的特定治疗方法。我们最近报道，硫化氢（HS）对 DACD 具有治疗潜力，但潜在机制尚未完全阐明。沉默信息调节因子 1（SIRT1）已被证明在调节糖尿病的进展中发挥作用，对于记忆形成和认知表现也是必不可少的。因此，本研究旨在探讨 SIRT1 是否通过抑制海马 ER 应激和突触功能障碍来介导 HS 对链脲佐菌素（STZ）诱导的认知功能障碍（DACD 的体内大鼠模型）的保护作用。结果表明，外源性 HS 供体 NaHS 给药增加了 STZ 诱导的糖尿病大鼠海马中的 SIRT1 表达。然后，结果证明 SIRT1 的特异性阻断剂 sirtinol 消除了 NaHS 对 STZ 诱导的认知功能障碍的抑制作用，通过 Morris 水迷宫测试、Y 迷宫测试和新物体识别行为测试进行评估。此外，NaHS 的给药消除了 STZ 诱导的 ER 应激，这表现在海马中 ER 应激相关蛋白（包括葡萄糖调节蛋白 78、C/EBP 同源蛋白和切割的半胱天冬酶-12）的表达减少，而这些 NaHS 的作用也被 sirtinol 逆转。此外，NaHS 诱导的突触相关蛋白（突触素-1、SYN1）在 STZ 诱导的糖尿病大鼠海马中的表达上调也被 sirtinol 消除。综上所述，这些结果表明 SIRT1 通过抑制海马 ER 应激和突触功能障碍，介导 HS 对 STZ 糖尿病大鼠认知功能障碍的保护作用。
