Division of Fundamental Neurobiology, Toronto Western Research Institute, Toronto, Ontario, Canada.
J Neurochem. 2010 May;113(4):826-35. doi: 10.1111/j.1471-4159.2010.06645.x. Epub 2010 Feb 15.
The ketogenic diet (KD), used successfully to treat a variety of epilepsy syndromes in humans and to attenuate seizures in different animal models, also provides powerful neuroprotection in various CNS injury models. Yet, a direct role for ketone bodies in limiting seizure and neuronal damage remains poorly understood. Using organotypic hippocampal slice cultures, we established an in vitro model of chronic ketosis for parallel studies of its neuroprotective and anti-convulsant effects. Chronic in vitro treatment with a ketone body, D-beta-hydroxybutyrate, protected the cultures against chronic hypoglycemia, oxygen-glucose deprivation, and NMDA-induced excitotoxicity, but failed to suppress intrinsic and induced seizure-like activity, indicating improved neuroprotection is not directly translated into seizure control. However, chronic in vitro ketosis abolished hippocampal network hyperexcitability following a metabolic insult, hypoxia, demonstrating for the first time a direct link between metabolic resistance and better control of excessive, synchronous, abnormal electrical activity. These findings suggest that the KD and, possibly, exogenous ketone administration, can be more beneficial for the treatment of seizures associated with metabolic stress or underlying metabolic abnormalities, and can potentially be used to optimize clinical applications of the traditional KD or its variants.
生酮饮食（KD）在人类中成功用于治疗各种癫痫综合征，并减轻不同动物模型中的癫痫发作，同时在各种中枢神经系统损伤模型中提供强大的神经保护作用。然而，酮体在限制癫痫发作和神经元损伤中的直接作用仍知之甚少。我们使用器官型海马切片培养物，建立了慢性酮症的体外模型，用于平行研究其神经保护和抗惊厥作用。慢性体外给予酮体 D-β-羟丁酸可保护培养物免受慢性低血糖、氧葡萄糖剥夺和 NMDA 诱导的兴奋性毒性，但未能抑制内在和诱导的癫痫样活动，表明改善的神经保护作用并未直接转化为癫痫发作的控制。然而，慢性体外酮症消除了代谢损伤、缺氧后海马网络的过度兴奋，首次证明代谢抵抗与过度、同步、异常电活动的更好控制之间存在直接联系。这些发现表明 KD 以及可能的外源性酮体给药可能更有益于治疗与代谢应激或潜在代谢异常相关的癫痫发作，并可能有助于优化传统 KD 或其变体的临床应用。
