Oxidative stress induces the decline of brain EPO expression in aging rats
Oxidative stress induces the decline of brain EPO expression in aging rats
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氧化应激导致衰老大鼠脑EPO表达下降
DOI：
10.1016/j.exger.2016.07.012
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发表时间：
2016-10-01
影响因子：
3.9
通讯作者：
Xu, Xiaoyu
中科院分区：
文献类型：
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作者：
Li, Xu;Chen, Yubao;Xu, Xiaoyu
脑促红细胞生成素(EPO)是一种重要的神经营养因子和神经保护因子，与衰老密切相关。研究发现，与青年大鼠相比，老年大鼠海马区EPO的表达明显降低。但大脑促红细胞生成素在衰老过程中下降的机制尚不清楚。本研究采用D-半乳糖(D-Gal)诱导的以氧化损伤为主的衰老模型，探讨衰老大鼠脑内促红细胞生成素(EPO)下降的机制。D-半乳糖致衰老大鼠(2月龄)每日皮下注射D-半乳糖50 mg·kg(-1)、150 mg·kg(-1)、250 mg·kg(-1)，连续8周，对照组仅给予赋形剂。这些组均与未接受其他治疗的老龄大鼠(24月龄)进行比较。用Morris水迷宫(MWM)评价模型大鼠的认知功能障碍，用试剂盒检测大鼠海马区β-半乳糖苷酶活性、脂质过氧化产物丙二醛(MDA)含量和超氧化物歧化酶(SOD)活性。免疫印迹法检测大鼠海马区EPO、EPOR、p-JAK2和缺氧诱导因子-2α(HIF-2α)的表达。此外，还分析了EPO/EPOR表达与丙二醛水平的相关系数。MWM测试显示，与对照组相比，150 mg·kg(-1)和250 mg·kg(-1)剂量组小鼠逃避潜伏期明显延长，穿越平台次数明显减少(p<0.05)。海马区β-半乳糖苷酶含量和丙二醛含量显著增加，超氧化物歧化酶活性显著降低(P<0.05，0.01和0.01)。与衰老大鼠相似，D-半乳糖150 mg·kg~(-1)和250 mg·kg~(-1)能显著降低脑内EPO、EPOR、p-JAK2和HIF-2α的表达(p<；0.05)。有趣的是，EpoR(r=-0.699，p<0.01)、EPO(r=-0.701，p<0.01)与丙二醛水平呈负相关。这些结果表明，衰老可导致海马区EPO含量下降，氧化应激可能是衰老大鼠脑内EPO含量下降的主要原因，并与HIF-2α稳定性降低有关。(C)2016 Elsevier Inc.保留所有权利。
Brain Erythropoietin (EPO), an important neurotrophic factor and neuroprotective factor, was found to be associated with aging. Studies found EPO expression was significantly decreased in the hippocampus of aging rat compared with that of the youth. But mechanisms of the decline of the brain EPO during aging remain unclear. The present study utilized a D-galactose (D-gal)-induced aging model in which the inducement of aging was mainly oxidative injury, to explore underlying mechanisms for the decline of brain EPO in aging rats. D-gal-induced aging rats (2 months) were simulated by subcutaneously injecting with D-gal at doses of 50 mg.kg(-1), 150 mg.kg(-1) and 250 mg.kg(-1) daily for 8 weeks while the control group received vehicle only. These groups were all compared with the aging rats (24 months) which had received no other treatment. The cognitive impairment was assessed using Morris water maze (MWM) in the prepared models, and the amount of beta-galactosidase, the lipid peroxidation product malondialdehyde (MDA) level and the superoxide dismutase (SOD) activity in the hippocampus was examined by assay kits. The levels of EPO, EPOR, p-JAK2 and hypoxia-inducible factor-2 alpha (HIF-2 alpha) in the hippocampus were detected by western blot. Additionally, the correlation coefficient between EPO/EPOR expression and MDA level was analyzed. The MWM test showed that compared to control group, the escape latency was significantly extended and the times of crossing the platform was decreased at the doses of 150 mg.kg(-1) and 250 mg.kg(-1) (p < 0.05). Also, the amount of beta-galactosidase and the MDA level in the hippocampus were significantly increased but the SOD activity was significantly decreased (p < 0.05, 0.01 and 0.01, respectively). Similar to aging rats, the expressions of EPO, EPOR, p-JAK2, and HIF-2 alpha in the brain of D-gal-treated rats were significantly decreased (p < 0.05) at 150 mg.kg(-1) and 250 mg.kg(-1). Interestingly, negative correlations were found between EPOR (r = -0.699, p < 0.01), EPO (r = -0.701, p < 0.01) and the MDA level. These results indicated that aging could result in the decline of EPO in the hippocampus and oxidative stress might be the main reason for the decline of brain EPO in aging rats, involved with the decrease of HIF-2 alpha stability. (C) 2016 Elsevier Inc. All rights reserved.