Ketogenic diet change cPLA2/clusterin and autophagy related gene expression and correlate with cognitive deficits and hippocampal MFs sprouting following neonatal seizures
Ketogenic diet change cPLA2/clusterin and autophagy related gene expression and correlate with cognitive deficits and hippocampal MFs sprouting following neonatal seizures
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生酮饮食改变 cPLA2/簇蛋白和自噬相关基因表达，并与认知缺陷和新生儿癫痫发作后海马 MF 萌芽相关
DOI：
10.1016/j.eplepsyres.2015.11.021
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发表时间：
2016-02-01
影响因子：
2.2
通讯作者：
Tian, Tian
中科院分区：
文献类型：
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作者：
Ni, Hong;Zhao, Dong-jing;Tian, Tian
由于生酮饮食（KD）影响海马能量代谢相关基因的表达，并且还发现脂膜过氧化及其相关的自噬应激也参与能量消耗，因此我们假设KD可能通过脂膜过氧化和自噬信号发挥其神经保护作用。在这里，我们通过检查新生儿癫痫发作和慢性KD治疗后脂质膜过氧化物相关的cPLA 2和clusterin，其下游自噬标记物Beclin-1，LC 3和p62以及其执行分子组织蛋白酶-E的长期表达来验证这一假设。出生后第9天（P9），将48只SD大鼠随机分为2组：氟乙烯诱发癫痫组和对照组。P28时，再随机分为癫痫发作组（RS + ND）、癫痫发作加生酮饮食组（RS + KD）、对照组（NS + ND）和对照组（NS + KD）。于P37、P43进行Morris水迷宫实验。采用Timm染色法检测苔藓纤维发芽情况，Western blot法检测蛋白质水平。氟乙烯诱导的RS + ND大鼠表现出长期较低的cPLA 2和LC 3 II/I含量，以及较高的clusterin、Beclin-1、p62和Cathepsin-E含量，这些与海马苔藓纤维发芽和认知缺陷平行。此外，慢性KD治疗（RS + KD）可有效恢复这些分子、神经病理学和认知变化。结果提示，新生儿惊厥后海马苔藓纤维出芽和认知功能障碍可能与脂质膜过氧化和自噬相关，这可能是KD治疗新生儿惊厥性脑损伤的潜在靶点。(C)2015爱思唯尔B. V.保留所有权利。
Because the ketogenic diet (KD) was affecting expression of energy metabolism- related genes in hippocampus and because lipid membrane peroxidation and its associated autophagy stress were also found to be involved in energy depletion, we hypothesized that KD might exert its neuroprotective action via lipid membrane peroxidation and autophagic signaling. Here, we tested this hypothesis by examining the long-term expression of lipid membrane peroxidation-related cPLA2 and clusterin, its downstream autophagy marker Beclin-1, LC3 and p62, as well as its execution molecule Cathepsin-E following neonatal seizures and chronic KD treatment. On postnatal day 9 (P9), 48 Sprague-Dawley rats were randomly assigned to two groups: flurothyl-induced recurrent seizures group and control group. On P28, they were further randomly divided into the seizure group without ketogenic diet (RS + ND), seizure plus ketogenic diet (RS + KD), the control group without ketogenic diet (NS + ND), and the control plus ketogenic diet (NS + KD). Morris water maze test was performed during P37 P43. Then mossy fiber sprouting and the protein levels were detected by Timm staining and Western blot analysis, respectively. Flurothyl-induced RS + ND rats show a long-term lower amount of cPLA2 and LC3II/I, and higher amount of clusterin, Beclin-1, p62 and Cathepsin-E which are in parallel with hippocampal mossy fiber sprouting and cognitive deficits. Furthermore, chronic KD treatment (RS + KD) is effective in restoring these molecular, neuropathological and cognitive changes. The results imply that a lipid membrane peroxidation and autophagy-associated pathway is involved in the aberrant hippocampal mossy fiber sprouting and cognitive deficits following neonatal seizures, which might be a potential target of KD for the treatment of neonatal seizure-induced brain damage. (C) 2015 Elsevier B.V. All rights reserved.