Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B
Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B
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二甲双胍通过下调 MAD2B 保护神经元免受缺氧/复氧诱导的损伤
DOI：
10.1159/000452562
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发表时间：
2016-01-01
影响因子：
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通讯作者：
Zhang, Chun
中科院分区：
文献类型：
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作者：
Meng, Xianfang;Chu, Guangpin;Zhang, Chun
背景/目的：二甲双胍是II型糖尿病的常用药物，对脑缺血具有保护作用。然而，其分子机制还远不清楚。有丝分裂阻滞缺陷2样蛋白2（MAD 2B）是一种晚期促进复合物（APC）的抑制剂，广泛表达于海马和皮层神经元，在高浓度葡萄糖诱导的神经毒性中起重要作用。本研究探讨了二甲双胍是否改变MAD 2B的表达，并发挥其神经保护作用，在原代培养的皮层神经元在氧-葡萄糖剥夺/复氧（OGD/R），广泛使用的体外缺血/再灌注模型。方法：原代培养大鼠皮层神经元，缺氧缺糖1h，恢复12 h和24 h。通过检测培养基中乳酸脱氢酶（LDH）的水平来测量细胞活力。Western blot检测细胞内MAD 2 B、cyclin B和p-histone 3的表达。结果：缺氧缺糖/复氧（OGD/R）条件下，神经元细胞活力降低。在OGD/R条件下，MAD 2B的表达增加。APC的底物细胞周期蛋白B1的水平也增加。此外，OGD/R上调组蛋白3的磷酸化水平，这是诱导有丝分裂后神经元的异常再进入。然而，二甲双胍预处理神经元可减轻OGD/R诱导的损伤。二甲双胍进一步降低MAD 2B、细胞周期蛋白B1的表达和组蛋白3的磷酸化水平。结论：二甲双胍通过调节缺氧缺糖/复氧损伤神经元MAD 2B的表达发挥神经保护作用。
Background/Aims: Metformin, the common medication for type II diabetes, has protective effects on cerebral ischemia. However, the molecular mechanisms are far from clear. Mitotic arrest deficient 2-like protein 2 (MAD2B), an inhibitor of the anaphase-promoting complex (APC), is widely expressed in hippocampal and cortical neurons and plays an important role in mediating high glucose-induced neurotoxicity. The present study investigated whether metformin modifies the expression of MAD2B and to exert its neuroprotective effects in primary cultured cortical neurons during oxygen-glucose deprivation/reoxygenation (OGD/R), a widely used in vitro model of ischemia/reperfusion. Methods: Primary cortical neurons were cultured, deprived of oxygen-glucose for 1 h, and then recovered with oxygen-glucose for 12 h and 24 h. Cell viability was measured by detecting the levels of lactate dehydrogenase (LDH) in culture medium. The levels of MAD2B, cyclin B and p-histone 3 were measured by Western blot. Results: Cell viability of neurons was reduced under oxygen-glucose deprivation/reoxygenation (OGD/R). The expression of MAD2B was increased under OGD/R. The levels of cyclin B1, which is a substrate of APC, were also increased. Moreover, OGD/R up-regulated the phosphorylation levels of histone 3, which is the induction of aberrant re-entry of post-mitotic neurons. However, pretreatment of neurons with metformin alleviated OGD/R-induced injury. Metformin further decreased the expression of MAD2B, cyclin B1 and phosphorylation levels of histone 3. Conclusion: Metformin exerts its neuroprotective effect through regulating the expression of MAD2B in neurons under OGD/R.