Systemic Lipopolysaccharide Administration-Induced Cognitive Impairments are Reversed by Erythropoietin Treatment in Mice
Systemic Lipopolysaccharide Administration-Induced Cognitive Impairments are Reversed by Erythropoietin Treatment in Mice
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DOI：
10.1007/s10753-015-0175-4
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发表时间：
2015-10-01
期刊：
影响因子：
5.1
通讯作者：
Zhu, Si-hai
中科院分区：
文献类型：
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作者：
Gao, Rong;Tang, Yuan-hui;Zhu, Si-hai
脓毒症相关脑病（SAE）是危重患者的常见并发症，与长期认知障碍相关。然而，对SAE的病理生理学基础了解甚少，缺乏药物治疗。本研究旨在探讨促红细胞生成素（EPO）对脂多糖（LPS）诱导的SAE动物模型认知功能障碍的影响。将小鼠随机分为假手术+赋形剂组、假手术+ EPO组、LPS +赋形剂组和LPS + EPO组。EPO在LPS给药后30 min给药，此后每天给药，持续2天。在第6天和第7天分别进行旷场和恐惧条件反射测试的行为测试。采用Kaplan-Meier法估计生存率。在指定的时间点测量海马中促炎症反应、氧化应激和细胞凋亡相关标志物的水平。透射电镜观察海马CA 1区突触形态计量学变化。我们的研究结果表明，LPS给药导致高死亡率和认知障碍，伴随着白细胞介素-1 β，丙二醛，裂解的caspase-3的表达增加，海马突触形态计量学异常的变化。值得注意的是，EPO治疗逆转了认知障碍并挽救了LPS给药诱导的脑病理学。总之，我们的数据表明，在SAE动物模型中，EPO治疗降低了死亡率，改善了认知障碍。
Sepsis-associated encephalopathy (SAE) is a frequent complication in critically ill patients and is associated with long-term cognitive impairments. However, the pathophysiology underlying SAE is poorly understood and the pharmacologic treatment is lacking. The purpose of the present study was to investigate the effects of erythropoietin (EPO) on cognitive impairments in an animal model of SAE induced by peripheral administration of lipopolysaccharide (LPS). Mice were randomly divided into the sham + vehicle, sham + EPO, LPS + vehicle, and LPS + EPO groups. EPO was administrated 30 min after the LPS administration and daily afterward for 2 days. Behavioral tests were performed on days 6 and 7 with open field and fear conditioning tests, respectively. The survival rate was estimated by the Kaplan-Meier method. The levels of proinflammatory responses, oxidative stress, and apoptosis-related markers were measured in the hippocampus at the indicated time points. The synaptic morphometry changes in the CA1 region were observed with transmission electron microscopy. Our results showed that LPS administration resulted in high mortality rate and cognitive impairments, which were accompanied by increased expressions of interleukin-1 beta, malondialdehyde, cleaved caspase-3, and abnormal synaptic morphometry changes in the hippocampus. Notably, EPO treatment reversed the cognitive impairments and rescued the brain pathology induced by LPS administration. In conclusion, our data suggested that treatment with EPO reduced the mortality rate and ameliorated cognitive impairments in an animal model of SAE.