Ketogenic diet sensitizes glucose control of hippocampal excitability
Ketogenic diet sensitizes glucose control of hippocampal excitability
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DOI：
10.1194/jlr.m046755
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发表时间：
2014-11-01
影响因子：
6.5
通讯作者：
Masino, Susan A.
中科院分区：
文献类型：
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作者：
Kawamura, Masahito, Jr.;Ruskin, David N.;Masino, Susan A.
高脂肪低碳水化合物生酮饮食（KD）是治疗难治性癫痫的有效方法，但体内无数的代谢效应与神经元效应尚未明确一致。KD限制血糖并从脂质的β-氧化产生酮体。研究已经探索了酮体和/或葡萄糖在KD效应中的变化，并且葡萄糖越来越多地涉及神经系统疾病。为了研究改变的葡萄糖和KD的神经效应之间的相互作用，我们在体外给大鼠和小鼠喂食KD和限制的葡萄糖，同时检查急性海马切片的CA 3区。KD喂养的动物切片对葡萄糖的小生理变化敏感，并表现出降低的兴奋性和癫痫发作倾向。与临床观察结果相似，兴奋性降低依赖于维持血糖降低。从缺乏腺苷A（1）受体（A（1）Rs）的KD喂养小鼠获得的切片中不存在葡萄糖敏感性增强和兴奋性降低;在正常动物的切片中，KD的影响可以用泛连接蛋白-1通道、A（1）Rs或K-ATP通道的阻断剂逆转。总体而言，这些研究表明，KD通过海马中的嘌呤能机制使基于葡萄糖的兴奋性调节敏感化，从而将KD的关键代谢和直接神经效应联系起来。
A high-fat low-carbohydrate ketogenic diet (KD) is an effective treatment for refractory epilepsy, yet myriad metabolic effects in vivo have not been reconciled clearly with neuronal effects. A KD limits blood glucose and produces ketone bodies from beta-oxidation of lipids. Studies have explored changes in ketone bodies and/or glucose in the effects of the KD, and glucose is increasingly implicated in neurological conditions. To examine the interaction between altered glucose and the neural effects of a KD, we fed rats and mice a KD and restricted glucose in vitro while examining the seizure-prone CA3 region of acute hippocampal slices. Slices from KD-fed animals were sensitive to small physiological changes in glucose, and showed reduced excitability and seizure propensity. Similar to clinical observations, reduced excitability depended on maintaining reduced glucose. Enhanced glucose sensitivity and reduced excitability were absent in slices obtained from KD-fed mice lacking adenosine A(1) receptors (A(1)Rs); in slices from normal animals effects of the KD could be reversed with blockers of pannexin-1 channels, A(1)Rs, or K-ATP channels. Overall, these studies reveal that a KD sensitizes glucose-based regulation of excitability via purinergic mechanisms in the hippocampus and thus link key metabolic and direct neural effects of the KD.