Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet
Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet
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DOI：
10.1002/ana.20899
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发表时间：
2006-08-01
影响因子：
11.2
通讯作者：
Dingledine, Raymond J.
中科院分区：
文献类型：
--
作者：
Bough, Kristopher J.;Wetherington, Jonathon;Dingledine, Raymond J.
目的：生酮饮食（KD）的完全抗惊厥作用可能需要数周才能在大鼠中形成，这表明基因表达的改变也参与其中。KD通常用于儿科癫痫，但对青少年和成人也有效。我们的目标是使用微阵列和补充技术在青春期大鼠，以了解其抗惊厥effect.Methods：微阵列被用来定义的基因表达模式，在大鼠的海马喂养KD或控制饮食3周。还比较了对照组和KD组大鼠海马电子显微照片中线粒体轮廓的数量、所选能量代谢物和酶活性的水平以及低葡萄糖对突触传递的影响。最引人注目的是所有（n = 34）编码能量代谢酶的差异调节转录物和42种编码线粒体蛋白的转录物中的39种的协调上调，这伴随着线粒体谱数目的增加、较高的磷酸肌酸/肌酸比率、升高的谷氨酸水平和降低的糖原水平。与增加的能量储备一致，KD喂养的动物海马切片中的突触传递对低glucose.Interpretation具有抗性：这些数据表明，限制热量的KD增强了脑代谢。我们提出了一个抗惊厥机制的KD涉及线粒体生物合成导致增强替代能源储存。
Objective: The full anticonvulsant effect of the ketogenic diet (KD) can require weeks to develop in rats, suggesting that altered gene expression is involved. The KD typically is used in pediatric epilepsies, but is effective also in adolescents and adults. Our goal was to use microarray and complementary technologies in adolescent rats to understand its anticonvulsant effect.Methods: Microarrays were used to define patterns of gene expression in the hippocampus of rats fed a KD or control diet for 3 weeks. Hippocampi from control- and KD-fed rats were also compared for the number of mitochondrial profiles in electron micrographs, the levels of selected energy metabolites and enzyme activities, and the effect of low glucose on synaptic transmission.Results: Most striking was a coordinated upregulation of all (n = 34) differentially regulated transcripts encoding energy metabolism enzymes and 39 of 42 transcripts encoding mitochondrial proteins, which was accompanied by an increased number of mitochondrial profiles, a higher phosphocreatine/creatine ratio, elevated glutamate levels, and decreased glycogen levels. Consistent with increased energy reserves, synaptic transmission in hippocampal slices from KD-fed animals was resistant to low glucose.Interpretation: These data show that a calorie-restricted KD enhances brain metabolism. We propose an anticonvulsant mechanism of the KD involving mitochondrial biogenesis leading to enhanced alternative energy stores.