Targeting deficiencies in mitochondrial respiratory complex I and functional uncoupling exerts anti-seizure effects in a genetic model of temporal lobe epilepsy and in a model of acute temporal lobe seizures.
Targeting deficiencies in mitochondrial respiratory complex I and functional uncoupling exerts anti-seizure effects in a genetic model of temporal lobe epilepsy and in a model of acute temporal lobe seizures.
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DOI：
10.1016/j.expneurol.2013.11.005
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发表时间：
2014-01
影响因子：
5.3
通讯作者：
Simeone, Timothy A.
中科院分区：
文献类型：
--
作者：
Simeone, Kristina A.;Matthews, Stephanie A.;Samson, Kaeli K.;Simeone, Timothy A.
关键词：
线粒体通过提供能量（ATP）和维持突触前和突触后元件中活性氧（ROS）的正常浓度积极参与神经传递。在人类和动物癫痫中，由线粒体呼吸复合物（MRC）I驱动的ATP产生呼吸速率降低，抗氧化系统减弱，氧化损伤增加。我们报告说，MRCI驱动的呼吸和功能解偶联（诱导抗氧化机制）减少，H2 O2水平升高，从KO小鼠分离的线粒体。通过鱼藤酮在WT海马切片中实验性损害MRCI降低苔藓纤维-CA 3突触处的成对脉冲比（PPR）（类似于KO PPR），并在体外加剧类似于癫痫的事件。AATP每日治疗[由抗坏血酸（AA）、α-生育酚（T）、丙酮酸钠（P）组成的联合治疗，旨在协同靶向线粒体损伤]改善了KO小鼠的线粒体功能、苔藓纤维PPR，并降低了癫痫负荷指数（SBI）评分和癫痫发作发生率。AATP预处理降低KA诱导的癫痫发作的严重程度，导致WT小鼠100%免于严重强直-阵挛性癫痫发作。这些数据表明，恢复大脑中的生物能量稳态可能是颞叶癫痫的一个可行的抗癫痫发作靶点。
Mitochondria actively participate in neurotransmission by providing energy (ATP) and maintaining normative concentrations of reactive oxygen species (ROS) in both presynaptic and postsynaptic elements. In human and animal epilepsies, ATP-producing respiratory rates driven by mitochondrial respiratory complex (MRC) I are reduced, antioxidant systems are attenuated and oxidative damage is increased. We report that MRCI-driven respiration and functional uncoupling (an inducible antioxidant mechanism) are reduced and levels of H2O2 are elevated in mitochondria isolated from KO mice. Experimental impairment of MRCI in WT hippocampal slices via rotenone reduces paired-pulse ratios (PPRs) at mossy fiber-CA3 synapses (resembling KO PPRs), and exacerbates seizure-like events in vitro. Daily treatment with AATP [a combination therapy composed of ascorbic acid (AA), alpha-tocopherol (T), sodium pyruvate (P) designed to synergistically target mitochondrial impairments] improved mitochondrial functions, mossy fiber PPRs, and reduced seizure burden index (SBI) scores and seizure incidence in KO mice. AATP pretreatment reduced severity of KA-induced seizures resulting in 100% protection from the severe tonic-clonic seizures in WT mice. These data suggest that restoration of bioenergetic homeostasis in the brain may represent a viable anti-seizure target for temporal lobe epilepsy.
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DOI：
10.1523/jneurosci.0026-12.2012
发表时间：
2012-06-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Hall CN;Klein-Flügge MC;Howarth C;Attwell D
通讯作者：
Attwell D
影响因子：
5.3
作者：
CORBISIER, P;RAES, M;REMACLE, J
通讯作者：
REMACLE, J
影响因子：
--
作者：
Ko, Sang-Bae;Ortega-Gutierrez, Santiago;Mayer, Stephan A.
通讯作者：
Mayer, Stephan A.
影响因子：
5.6
作者：
Ayyildiz, Mustafa;Coskun, Sule;Agar, Erdal
通讯作者：
Agar, Erdal
影响因子：
5.3
作者：
Knapp, LT;Klann, E
通讯作者：
Klann, E