Hu Ying, Zhang Qin, Wang Jian-Cheng, Wang Jiao, Liu Ying, Zhu Ling-Yan, Xu Ji-Xiong
Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China.
Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, People's Republic of China.
Kaohsiung J Med Sci. 2023 Apr;39(4):404-415. doi: 10.1002/kjm2.12643. Epub 2023 Jan 18.
Resveratrol (RSV) has been shown to have a neuroprotective effect in various central nervous system disorders, although the role of RSV in diabetes-induced cognitive dysfunction is still not fully elucidated. Here, we investigated whether RSV improved diabetes-related cognitive dysfunction in vivo and in vitro. We induced a rat diabetic model with a high-fat and high-sucrose diet followed by intraperitoneal injection of streptozotocin and a diabetic neuron cell model by stimulation with high levels of glucose. We observed that RSV improved impairment in spatial learning and memory in the Morris water maze test (MWM) and novel object recognition test (ORT) in diabetic rats. RSV reversed the reduced miR-146a-5p and upregulated thioredoxin-interacting protein (TXNIP) and inhibited the diabetes-induced increase in interleukin (IL)-1β and tumor necrosis factor (TNF)-α levels in vivo and in vitro. RSV also inhibited diabetes-induced endoplasmic reticulum stress (ESR) by reducing ESR-related protein expression in vivo and in vitro. Moreover, inhibition of miR-146a-5p partially abolished the protective effects of RSV in HG-treated primary neurons. Additionally, we used starBase to predict that miR-146a-5p interacts with TXNIP, which we then verified using a luciferase reporter gene assay. We further observed that miR-146a-5p regulates the mRNA and protein expression of TXNIP in vitro, indicating that the miR-146a-5p/TXNIP axis is involved in the regulation of cognitive dysfunction in a rat diabetic model. Collectively, these results demonstrate that RSV plays a neuroprotective role in diabetes-associated cognitive dysfunction at least in part through regulation of the miR-146a-5p/TXNIP axis.
白藜芦醇（RSV）已被证明在各种中枢神经系统疾病中具有神经保护作用，尽管RSV在糖尿病诱导的认知功能障碍中的作用仍未完全阐明。在此，我们研究了RSV在体内和体外是否能改善糖尿病相关的认知功能障碍。我们通过高脂高糖饮食诱导大鼠糖尿病模型，随后腹腔注射链脲佐菌素，并通过高糖刺激建立糖尿病神经元细胞模型。我们观察到，RSV改善了糖尿病大鼠在莫里斯水迷宫试验（MWM）和新物体识别试验（ORT）中的空间学习和记忆障碍。RSV逆转了miR-146a-5p的降低，并上调了硫氧还蛋白相互作用蛋白（TXNIP），并在体内和体外抑制了糖尿病诱导的白细胞介素（IL）-1β和肿瘤坏死因子（TNF）-α水平的升高。RSV还通过在体内和体外降低内质网应激（ESR）相关蛋白的表达来抑制糖尿病诱导的内质网应激。此外，抑制miR-146a-5p部分消除了RSV对高糖处理的原代神经元的保护作用。此外，我们使用starBase预测miR-146a-5p与TXNIP相互作用，然后我们使用荧光素酶报告基因检测进行了验证。我们进一步观察到，miR-146a-5p在体外调节TXNIP的mRNA和蛋白表达，表明miR-146a-5p/TXNIP轴参与了大鼠糖尿病模型中认知功能障碍的调节。总的来说，这些结果表明，RSV至少部分通过调节miR-146a-5p/TXNIP轴在糖尿病相关的认知功能障碍中发挥神经保护作用。
