Yan Wenhui, Guo Tingli, Liu Na, Cui Xin, Wei Xiaotong, Sun Yuzhuo, Hu Hao, Chen Lina
Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, Shaanxi 710061, China.
Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
Cell Signal. 2023 Jun;106:110614. doi: 10.1016/j.cellsig.2023.110614. Epub 2023 Feb 3.
Recent studies have shown that erythropoietin (EPO) is an effective neuroprotective and neurotrophic agent for neurological disorders, such as traumatic brain injury and Alzheimer's disease. However, the effectiveness of EPO administration against diabetic cognitive impairments has rarely been examined. In this study, we investigated the effects of EPO on streptozotocin (STZ)-induced male C57BL/6 J mice. Then, we sought to clarify the mechanisms of EPO-mediated neuroprotection in high-glucose (HG)-stimulated HT22 cells. In vivo, we found that STZ-induced diabetic mice showed impaired spatial learning and memory, which was alleviated by EPO treatment. EPO also significantly lowered elevated fasting blood glucose levels, improved pancreatic and hippocampal damage, and restored oxidative stress in the STZ-induced diabetic mice. In vitro, EPO markedly increased cell viability, restrained the expression of pro-apoptotic Bax, enhanced the expression of pro-caspase 3, anti-apoptotic Bcl-2, brain-derived neurotrophic factor (BDNF) and postsynaptic density 95 (PSD-95), and attenuated the upregulation of N-methyl-d-aspartic acid (NMDA) receptor subunits NR1, NR2A and NR2B in HG-induced HT22 cells. The protective effects of EPO was obviously abolished by treatment with an NMDA receptor agonist. Our findings revealed that EPO impedes hippocampal and synaptic damage and neuronal apoptosis by regulating BDNF and PSD-95 expression through NMDA receptors, thereby ameliorating cognitive impairments in mice with T1DM.
最近的研究表明，促红细胞生成素（EPO）是一种有效的神经保护和神经营养剂，可用于治疗诸如创伤性脑损伤和阿尔茨海默病等神经系统疾病。然而，EPO给药对糖尿病认知障碍的有效性很少被研究。在本研究中，我们调查了EPO对链脲佐菌素（STZ）诱导的雄性C57BL/6 J小鼠的影响。然后，我们试图阐明EPO在高糖（HG）刺激的HT22细胞中介导神经保护的机制。在体内，我们发现STZ诱导的糖尿病小鼠表现出空间学习和记忆受损，而EPO治疗可缓解这种情况。EPO还显著降低了升高的空腹血糖水平，改善了胰腺和海马损伤，并恢复了STZ诱导的糖尿病小鼠的氧化应激。在体外，EPO显著提高细胞活力，抑制促凋亡蛋白Bax的表达，增强前体半胱天冬酶3、抗凋亡蛋白Bcl-2、脑源性神经营养因子（BDNF）和突触后密度蛋白95（PSD-95）的表达，并减弱HG诱导的HT22细胞中N-甲基-D-天冬氨酸（NMDA）受体亚基NR1、NR2A和NR2B的上调。用NMDA受体激动剂处理明显消除了EPO的保护作用。我们的研究结果表明，EPO通过NMDA受体调节BDNF和PSD-95的表达，从而阻止海马和突触损伤以及神经元凋亡，进而改善1型糖尿病小鼠的认知障碍。
