Gano Lindsey B, Patel Manisha, Rho Jong M
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado, Denver, CO.
Departments of Pediatrics and Clinical Neurosciences, Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada.
J Lipid Res. 2014 Nov;55(11):2211-28. doi: 10.1194/jlr.R048975. Epub 2014 May 20.
The ketogenic diet (KD) is a broad-spectrum therapy for medically intractable epilepsy and is receiving growing attention as a potential treatment for neurological disorders arising in part from bioenergetic dysregulation. The high-fat/low-carbohydrate "classic KD", as well as dietary variations such as the medium-chain triglyceride diet, the modified Atkins diet, the low-glycemic index treatment, and caloric restriction, enhance cellular metabolic and mitochondrial function. Hence, the broad neuroprotective properties of such therapies may stem from improved cellular metabolism. Data from clinical and preclinical studies indicate that these diets restrict glycolysis and increase fatty acid oxidation, actions which result in ketosis, replenishment of the TCA cycle (i.e., anaplerosis), restoration of neurotransmitter and ion channel function, and enhanced mitochondrial respiration. Further, there is mounting evidence that the KD and its variants can impact key signaling pathways that evolved to sense the energetic state of the cell, and that help maintain cellular homeostasis. These pathways, which include PPARs, AMP-activated kinase, mammalian target of rapamycin, and the sirtuins, have all been recently implicated in the neuroprotective effects of the KD. Further research in this area may lead to future therapeutic strategies aimed at mimicking the pleiotropic neuroprotective effects of the KD.
生酮饮食（KD）是一种针对药物难治性癫痫的广谱疗法，作为一种可能治疗部分由生物能量调节异常引起的神经疾病的方法，正受到越来越多的关注。高脂肪/低碳水化合物的“经典KD”，以及诸如中链甘油三酯饮食、改良阿特金斯饮食、低血糖指数疗法和热量限制等饮食变体，可增强细胞代谢和线粒体功能。因此，这类疗法广泛的神经保护特性可能源于细胞代谢的改善。临床和临床前研究数据表明，这些饮食会限制糖酵解并增加脂肪酸氧化，这些作用会导致酮症、三羧酸循环（即回补反应）的补充、神经递质和离子通道功能的恢复以及线粒体呼吸增强。此外，越来越多的证据表明，KD及其变体可影响关键的信号通路，这些信号通路进化而来以感知细胞的能量状态，并有助于维持细胞内稳态。这些通路包括过氧化物酶体增殖物激活受体（PPARs）、AMP激活的蛋白激酶、雷帕霉素靶蛋白以及沉默调节蛋白，最近都被认为与KD的神经保护作用有关。该领域的进一步研究可能会带来旨在模拟KD多效性神经保护作用的未来治疗策略。
