Prolonged seizure activity impairs mitochondrial bioenergetics and induces cell death.
Prolonged seizure activity impairs mitochondrial bioenergetics and induces cell death.
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DOI：
10.1242/jcs.099176
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发表时间：
2012-04-01
影响因子：
4
通讯作者：
Abramov AY
中科院分区：
文献类型：
--
作者：
Kovac S;Domijan AM;Walker MC;Abramov AY
过度活动（例如长时间癫痫发作期间发生的）导致神经元死亡的机制尚不清楚，但假设线粒体功能障碍发挥了作用。在这里，我们通过荧光成像技术在大鼠胶质神经元新皮质共培养物中进行了测试，使用低 Mg2+ 水平诱导癫痫样活动。 NMDA 受体的谷氨酸激活导致神经元中 Ca2+ 振荡和线粒体膜电位持续去极化，这对环孢素 A 敏感，表明线粒体通透性和过渡孔开放。它还依赖于谷氨酸释放和 NMDA 受体激活，因为用空泡型 H+-ATP 酶刀那霉素 A 耗尽囊泡谷氨酸或用 APV 阻断 NMDA 受体后，未观察到去极化。在长时间癫痫发作期间，体细胞和树突中的神经元 ATP 水平显着下降，并与振荡 Ca2+ 信号的频率相关，表明活动依赖性 ATP 消耗。在低 Mg2+ 条件下阻断线粒体复合物 I、复合物 V 或解偶联线粒体氧化磷酸化可加速活性依赖性神经元 ATP 消耗。与对照治疗相比，低 Mg2+ 水平 2 小时和 24 小时后神经元死亡增加，通过补充线粒体复合物 I 底物丙酮酸可减少神经元死亡。这些发现表明，线粒体功能障碍在癫痫活动诱发的神经元死亡中发挥着至关重要的作用，而旨在纠正这一问题的策略具有神经保护作用。
The mechanisms underlying neuronal death following excessive activity such as occurs during prolonged seizures are unclear, but mitochondrial dysfunction has been hypothesised to play a role. Here, we tested this with fluorescence imaging techniques in rat glioneuronal neocortical co-cultures using low Mg2+ levels to induce seizure-like activity. Glutamate activation of NMDA receptors resulted in Ca2+ oscillations in neurons and a sustained depolarisation of the mitochondrial membrane potential, which was cyclosporine A sensitive, indicating mitochondrial permeability and transition pore opening. It was also dependent on glutamate release and NMDA receptor activation, because depolarisation was not observed after depleting vesicular glutamate with vacuolar-type H+-ATPase concanamycin A or blocking NMDA receptors with APV. Neuronal ATP levels in soma and dendrites decreased significantly during prolonged seizures and correlated with the frequency of the oscillatory Ca2+ signal, indicative of activity-dependent ATP consumption. Blocking mitochondrial complex I, complex V or uncoupling mitochondrial oxidative phosphorylation under low-Mg2+ conditions accelerated activity-dependent neuronal ATP consumption. Neuronal death increased after two and 24 hours of low Mg2+ levels compared with control treatment, and was reduced by supplementation with the mitochondrial complex I substrate pyruvate. These findings demonstrate a crucial role for mitochondrial dysfunction in seizure-activity-induced neuronal death, and that strategies aimed at redressing this are neuroprotective.
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影响因子：
6.1
作者：
Lauritzen, Fredrik;de Lanerolle, Nihal C.;Lee, Tih-Shih W.;Spencer, Dennis D.;Kim, Jung H.;Bergersen, Linda H.;Eid, Tore
通讯作者：
Eid, Tore
影响因子：
5.3
作者：
Kovács, R;Kardos, J;Kann, O
通讯作者：
Kann, O
影响因子：
4.8
作者：
Huss, M;Ingenhorst, G;Wieczorek, H
通讯作者：
Wieczorek, H
影响因子：
5
作者：
Deshpande, Laxmikant S.;Lou, Jeffrey K.;DeLorenzo, Robert J.
通讯作者：
DeLorenzo, Robert J.
影响因子：
4.1
作者：
BRAND, MD
通讯作者：
BRAND, MD