Ketone bodies mediate antiseizure effects through mitochondrial permeability transition.
Ketone bodies mediate antiseizure effects through mitochondrial permeability transition.
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酮体通过线粒体渗透性过渡介导抗性作用。
DOI：
10.1002/ana.24424
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发表时间：
2015-07
影响因子：
11.2
通讯作者：
Rho, Jong M.
中科院分区：
文献类型：
--
作者：
Kim, Do Young;Simeone, Kristina A.;Simeone, Timothy A.;Pandya, Jignesh D.;Wilke, Julianne C.;Ahn, Younghee;Geddes, James W.;Sullivan, Patrick G.;Rho, Jong M.
酮体（KB）是脂肪酸氧化的产物，在禁食或高脂肪抗癫痫生酮饮食（KD）治疗期间作为必需燃料。尽管越来越多的证据表明KB发挥广泛的神经保护作用，但其在癫痫控制中的作用尚未得到证实。本研究的主要目的是证明KB的直接抗癫痫作用，并确定潜在的靶点机制。我们研究了KD和KB在自发性癫痫Kcna 1-null小鼠使用的行为，平面多电极，和标准的细胞电生理技术的组合的影响。在急性分离的脑线粒体中确定了线粒体渗透性转变（mPT）的阈值。仅KB就足以：（1）在Kcna 1缺失小鼠中发挥抗癫痫作用;（2）恢复Kcna 1缺失突变体中海马长时程增强（LTP）和空间学习记忆缺陷的内在损伤;（3）提高从Kcna 1缺失动物的海马急性制备的线粒体中钙诱导mPT的阈值。靶向删除mPT复合物的亲环素D（CypD）亚基消除了KB对mPT的作用，发现mPT的体内药理学抑制和激活分别反映和逆转了KD在Kcna 1缺失小鼠中的抗癫痫作用。目前的数据揭示了mPT和癫痫控制之间的第一个直接联系，并提供了一个潜在的机制解释KD。鉴于mPT越来越多地涉及各种神经系统疾病，我们的研究结果表明，代谢为基础的治疗和/或代谢底物可能代表了一个有价值的治疗发展的范例。
Ketone bodies (KB) are products of fatty acid oxidation and serve as essential fuels during fasting or treatment with the high-fat anti-seizure ketogenic diet (KD). Despite growing evidence that KB exert broad neuroprotective effects, their role in seizure control has not been firmly demonstrated. The major goal of this study was to demonstrate the direct anti-seizure effects of KB and to identify an underlying target mechanism. We studied the effects of both the KD and KB in spontaneously epileptic Kcna1-null mice using a combination of behavioral, planar multi-electrode, and standard cellular electophysiological techniques. Thresholds for mitochondrial permeability transition (mPT) were determined in acutely isolated brain mitochondria. KB alone were sufficient to: (1) exert anti-seizure effects in Kcna1-null mice; (2) restore intrinsic impairment of hippocampal long-term potentiation (LTP) and spatial learning-memory defects in Kcna1-null mutants; and (3) raise the threshold for calcium-induced mPT in acutely prepared mitochondria from hippocampi of Kcna1-null animals. Targeted deletion of the cyclophilin D (CypD) subunit of the mPT complex abrogated the effects of KB on mPT, and in vivo pharmacological inhibition and activation of mPT were found to mirror and reverse, respectively, the anti-seizure effects of the KD in Kcna1-null mice. The present data reveal the first direct link between mPT and seizure control, and provide a potential mechanistic explanation for the KD. Given that mPT is increasingly being implicated in diverse neurological disorders, our results suggest that metabolism-based treatments and/or metabolic substrates might represent a worthy paradigm for therapeutic development.
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影响因子：
4.2
作者：
Davis, Laurie M.;Pauly, James R.;Sullivan, Patrick G.
通讯作者：
Sullivan, Patrick G.
影响因子：
4
作者：
Kovac S;Domijan AM;Walker MC;Abramov AY
通讯作者：
Abramov AY
DOI：
10.1097/mco.0b013e3282f44c06
发表时间：
2008-03-01
影响因子：
3.1
作者：
Kim, Do Young;Rho, Jong M.
通讯作者：
Rho, Jong M.
影响因子：
4.8
作者：
Jiang, DM;Sullivan, PG;Weiss, JH
通讯作者：
Weiss, JH
影响因子：
2.2
作者：
Cock, HR;Tong, X;Walker, MC
通讯作者：
Walker, MC