The ATP-sensitive K channel is seizure protective and required for effective dietary therapy in a model of mitochondrial encephalomyopathy.
The ATP-sensitive K channel is seizure protective and required for effective dietary therapy in a model of mitochondrial encephalomyopathy.
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DOI：
10.1080/01677063.2016.1252765
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发表时间：
2016-09
影响因子：
1.9
通讯作者：
Palladino MJ
中科院分区：
文献类型：
--
作者：
Fogle KJ;Hertzler JI;Shon JH;Palladino MJ
线粒体脑肌病（ME）缺乏有效的治疗方法。 ME 是毁灭性的疾病，主要影响神经系统和肌肉的能量需求组织，引起癫痫、心肌病、神经和肌肉退化等症状。即使是经常成功改善其他疾病癫痫发作的常见抗癫痫药物，在 ME 中的成功率也往往较低，这凸显了对新药物靶点的需求，特别是那些可能将代谢敏感性与神经元兴奋性结合起来的药物靶点。此外，饮食调整等替代性癫痫疗法在临床上越来越受欢迎，但尚未在 ME 中得到彻底研究。使用 ME 的果蝇 ATP61 模型，我们研究了整个疾病进展的饮食疗法，发现它对 ME 的癫痫发作非常有效，尤其是高脂肪/生酮饮食，并且其益处取决于功能性 KATP 通道复合物。 KATP 的进一步实验表明，它在该模型中具有癫痫保护作用，并且其开放状态的药理学促进也可改善癫痫发作。这些研究代表了针对一类众所周知难以治疗的疾病开发新疗法的重要一步，并为代谢疾病背景下现有疗法的机制研究奠定了基础。
Effective therapies are lacking for mitochondrial encephalomyopathies (MEs). MEs are devastating diseases that predominantly affect the energy-demanding tissues of the nervous system and muscle, causing symptoms such as seizures, cardiomyopathy, and neuro- and muscular degeneration. Even common anti-epileptic drugs which are frequently successful in ameliorating seizures in other diseases tend to have a lower success rate in ME, highlighting the need for novel drug targets, especially those that may couple metabolic sensitivity to neuronal excitability. Furthermore, alternative epilepsy therapies such as dietary modification are gaining in clinical popularity but haven't been thoroughly studied in ME. Using the Drosophila ATP61 model of ME, we have studied dietary therapy throughout disease progression and found that it is highly effective against the seizures of ME, especially a high fat/ketogenic diet, and that the benefits are dependent upon a functional KATP channel complex. Further experiments with KATP show that it is seizure-protective in this model, and that pharmacological promotion of its open state also ameliorates seizures. These studies represent important steps forward in the development of novel therapies for a class of diseases that is notoriously difficult to treat, and lay the foundation for mechanistic studies of currently existing therapies in the context of metabolic disease.
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DOI：
10.1152/ajpheart.00366.2006
发表时间：
2007-02-01
影响因子：
4.8
作者：
Comelli, Marina;Metelli, Giuliana;Mavelli, Irene
通讯作者：
Mavelli, Irene
影响因子：
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作者：
DUNNE, MJ;PETERSEN, OH
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DOI：
10.1007/bf00195964
发表时间：
1992-08-01
影响因子：
2.1
作者：
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通讯作者：
WU, CF
DOI：
10.1073/pnas.1416586112
发表时间：
2015-02-17
影响因子：
11.1
作者：
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通讯作者：
Holmes, Todd C.
影响因子：
5.6
作者：
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Rogawski, Michael A.