Han Yu-Fei, Holscher Christian, Wang Zhao-Jun, Zhang Jun, Yuan Li, Tong Jia-Qing, Wang Dan-Dan, Wu Mei-Na, Qi Jin-Shun
Department of Physiology, Key Laboratory for Cellular Physiology of Ministry of Education, Shanxi Medical University, Taiyuan 030001, China.
Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK.
Sheng Li Xue Bao. 2016 Jun 25;68(3):265-75.
The accumulation and neurotoxicity of amyloid β protein (Aβ) in the brain is one of major pathological hallmarks of Alzheimer's disease (AD). The effective drugs against Aβ have been still deficient up to now. According to a most recent study, (D-Ser2) Oxm, a new antidiabetic drug, not only improves the disorders in plasma glucose and insulin in type 2 diabetes mellitus (T2DM) rats, but also exerts positive effects on hippocampal neurogenesis and synaptogenesis. However, it is still unclear whether (D-Ser2)Oxm can directly protect cultured neurons against Aβ1-42-induced cytotoxicity. In the present study, we investigated the neuroprotective effects of (D-Ser2)Oxm on the cultured primary hippocampal neurons by testing the cell viability, neuronal apoptosis, mitochondrial membrane potential and intracellular calcium concentration. The results showed that treatment with (D-Ser2)Oxm effectively reversed Aβ1-42-induced decline in cell viability (P < 0.001), and this protective effect could be inhibited by the pretreatment with exendin(9-39), a GLP-1 receptor blocker. (D-Ser2)Oxm treatment also decreased Aβ1-42-induced neuronal early apoptosis and down-regulated apoptotic protein caspase3. Meantime, (D-Ser2)Oxm treatment inhibited Aβ1-42-induced [Ca(2+)]i elevation, mitochondrial membrane potential depolarization, and glycogen synthase kinase-3β (GSK3β) activation. These results suggest that (D-Ser2)Oxm can protect hippocampal neurons against Aβ1-42-induced cytotoxicity and this effect may be related to activation of GLP-1 receptors, regulation of intracellular calcium homeostasis and stabilization of mitochondrial membrane potential.
淀粉样β蛋白（Aβ）在大脑中的积累及其神经毒性是阿尔茨海默病（AD）的主要病理特征之一。迄今为止，针对Aβ的有效药物仍然不足。根据最近一项研究，新型抗糖尿病药物（D-Ser2）奥曲肽不仅能改善2型糖尿病（T2DM）大鼠的血糖和胰岛素紊乱，还对海马神经发生和突触形成具有积极作用。然而，（D-Ser2）奥曲肽是否能直接保护培养的神经元免受Aβ1-42诱导的细胞毒性仍不清楚。在本研究中，我们通过检测细胞活力、神经元凋亡、线粒体膜电位和细胞内钙浓度，研究了（D-Ser2）奥曲肽对原代培养海马神经元的神经保护作用。结果表明，（D-Ser2）奥曲肽处理可有效逆转Aβ1-42诱导的细胞活力下降（P < 0.001），且这种保护作用可被胰高血糖素样肽-1（GLP-1）受体阻断剂艾塞那肽（9-39）预处理所抑制。（D-Ser2）奥曲肽处理还可减少Aβ1-42诱导的神经元早期凋亡，并下调凋亡蛋白半胱天冬酶3。同时，（D-Ser2）奥曲肽处理可抑制Aβ1-42诱导引起的细胞内钙离子浓度升高、线粒体膜电位去极化以及糖原合酶激酶-3β（GSK3β）激活。这些结果表明，（D-Ser2）奥曲肽可保护海马神经元免受Aβ1-42诱导的细胞毒性，且这种作用可能与GLP-1受体激活、细胞内钙稳态调节以及线粒体膜电位稳定有关。
