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淀粉样β蛋白(amyloidβ-protein,Aβ)在脑内的沉积及其神经毒性是阿尔茨海默病(Alzheimer’s disease,AD)的主要原因之一,目前仍缺乏拮抗Aβ的有效药物。最新报道表明,一种新的抗糖尿病药物(D-Ser2)Oxm不仅可以改善2型糖尿病(T2DM)大鼠的血糖和胰岛素水平,也具有促进皮层和海马神经元及其突触发生的效应。然而,(D-Ser2)Oxm是否能拮抗AD时Aβ所致的细胞损伤仍缺乏实验依据。本研究在培养原代大鼠海马神经细胞基础上,通过细胞活性和早期凋亡测定、细胞内钙成像以及线粒体膜电位检测,研究了(D-Ser2)Oxm对Aβ1-42所致细胞毒性的拮抗效应。结果显示,与单独给予Aβ1-42处理的细胞相比,(D-Ser2)Oxm+Aβ1-42处理组的细胞活力明显提高,而加入GLP-1受体抑制剂exendin(9-39)后,细胞活力则显著下降;(D-Ser2)Oxm可有效拮抗Aβ1-42导致的细胞凋亡,并使凋亡相关蛋白caspase3含量显著降低;(D-Ser2)Oxm处理还有效阻止了Aβ1-42引起的海马细胞内钙水平升高、线粒体膜电位去极化以及糖原合成酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)(Y216)的活化。以上结果表明,(D-Ser2)Oxm可能是通过激动GLP-1受体对抗Aβ1-42的神经毒性,并且这种保护效应可能与细胞内钙稳态调节和线粒体膜电位稳定有关。
The deposition and neurotoxicity of amyloid β-protein (Aβ) in the brain is one of the major causes of Alzheimer’s disease (AD). Currently, there is still no effective drug to antagonize Aβ. Recent reports indicate that a new antidiabetic drug, Ox-D, not only improves blood glucose and insulin levels in type 2 diabetic rats, but also promotes cortical and hippocampal neurons and their synaptic effects. However, whether (D-Ser2) Oxm can antagonize Aβ-induced cell injury in AD is still lack of experimental evidence. In this study, primary cultured rat hippocampal neurons were cultured on the basis of cell viability and early apoptosis assay, intracellular calcium imaging and mitochondrial membrane potential assay, (D-Ser2) Oxm Aβ1-42 induced cytotoxicity Antagonistic effect. The results showed that the cell viability of (D-Ser2) Oxm + Aβ1-42 treatment group was significantly increased compared with the cells treated with Aβ1-42 alone. After addition of the GLP-1 receptor inhibitor exendin (9-39) (D-Ser2) Oxm effectively antagonized the apoptosis induced by Aβ1-42, and significantly decreased the content of caspase3. (D-Ser2) Oxm treatment also effectively prevented Aβ1-42-induced apoptosis , Increased mitochondrial membrane potential depolarization and activation of glycogen synthase kinase-3β (Y216) in hippocampus. The above results indicate that (D-Ser2) Oxm may be neurotoxic against Aβ 1-42 by agonizing GLP-1 receptor, and this protective effect may be related to intracellular calcium homeostasis and mitochondrial membrane potential stabilization.