Status Epilepticus in Immature Rats Is Associated with Oxidative Stress and Mitochondrial Dysfunction.
Status Epilepticus in Immature Rats Is Associated with Oxidative Stress and Mitochondrial Dysfunction.
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DOI：
10.3389/fncel.2016.00136
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发表时间：
2016
影响因子：
5.3
通讯作者：
Otáhal J
中科院分区：
文献类型：
--
作者：
Folbergrová J;Ješina P;Kubová H;Druga R;Otáhal J
癫痫是一种神经系统疾病，在婴儿和儿童中尤其常见，可能会在以后的生活中导致严重后果。氧化应激和线粒体功能障碍与许多神经系统疾病（包括成人癫痫）的发病机制有关。然而，它们在未成熟癫痫大脑中的作用尚不清楚，因为存在两种相反的观点：氧化应激是年龄依赖性的，并且在癫痫持续状态（SE）期间不会发生在未成熟大脑中，另一方面，在特定的 SE 模型中未成熟大脑中存在氧化应激的证据。为了解决这一困境，我们决定研究三种具有不同作用机制的物质（即 4-氨基吡啶、LiCl-毛果芸香碱或红藻氨酸）在未成熟的 12 日龄大鼠中诱导 SE 后的氧化应激。 Fluoro-Jade-B 染色显示每个测试模型都有轻微的脑损伤，尤其是海马体和丘脑。葡萄糖和糖原的减少与乳酸的平行上升清楚地表明糖酵解率较高，这在 4-AP 和 Li-Pilo 状态下显然是不够的，从 PCr 水平的降低可以明显看出。 Hydroethidium 方法显示，未成熟大鼠在状态期间的海马、大脑皮层和丘脑中超氧阴离子水平显着升高（约 60%）。 SE 导致线粒体功能障碍，复合物 I 活性显着降低，并持续很长一段时间。配合物 II 和 IV 的活性仍处于对照范围内。使用 SOD 模拟物 MnTMPYP 或过氧亚硝酸盐清除剂 FeTPPS 进行抗氧化处理可显着减轻氧化应激和复合物 I 活性的抑制。这些发现证明氧化应激和线粒体功能障碍与年龄和模型无关，因此可能被认为是一种普遍现象。它们可以与治疗癫痫的新方法具有临床相关性，从而能够针对在婴儿和儿童癫痫发病机制中发挥关键或附加作用的机制。
Epilepsy is a neurologic disorder, particularly frequent in infants and children where it can lead to serious consequences later in life. Oxidative stress and mitochondrial dysfunction are implicated in the pathogenesis of many neurological disorders including epilepsy in adults. However, their role in immature epileptic brain is unclear since there have been two contrary opinions: oxidative stress is age-dependent and does not occur in immature brain during status epilepticus (SE) and, on the other hand, evidence of oxidative stress in immature brain during a specific model of SE. To solve this dilemma, we have decided to investigate oxidative stress following SE induced in immature 12-day-old rats by three substances with a different mechanism of action, namely 4-aminopyridine, LiCl-pilocarpine or kainic acid. Fluoro-Jade-B staining revealed mild brain damage especially in hippocampus and thalamus in each of the tested models. Decrease of glucose and glycogen with parallel rises of lactate clearly indicate high rate of glycolysis, which was apparently not sufficient in 4-AP and Li-Pilo status, as evident from the decreases of PCr levels. Hydroethidium method revealed significantly higher levels of superoxide anion (by ∼60%) in the hippocampus, cerebral cortex and thalamus of immature rats during status. SE lead to mitochondrial dysfunction with a specific pronounced decrease of complex I activity that persisted for a long period of survival. Complexes II and IV activities remained in the control range. Antioxidant treatment with SOD mimetic MnTMPYP or peroxynitrite scavenger FeTPPS significantly attenuated oxidative stress and inhibition of complex I activity. These findings bring evidence that oxidative stress and mitochondrial dysfunction are age and model independent, and may thus be considered a general phenomenon. They can have a clinical relevance for a novel approach to the treatment of epilepsy, allowing to target the mechanisms which play a crucial or additive role in the pathogenesis of epilepsies in infants and children.