Mitochondrial dysfunction associated with neuronal death following status epilepticus in rat
Mitochondrial dysfunction associated with neuronal death following status epilepticus in rat
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DOI：
10.1016/s0920-1211(01)00334-5
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发表时间：
2002-02-01
影响因子：
2.2
通讯作者：
Walker, MC
中科院分区：
文献类型：
--
作者：
Cock, HR;Tong, X;Walker, MC
在人类和动物模型中，癫痫持续状态（SE）会导致严重的脑损伤和随后癫痫发作的风险增加，并伴有神经元丢失的特征性模式，特别是影响海马。癫痫相关的细胞死亡被认为是兴奋性毒性的，但研究有限，主要集中在终末事件而不是初始机制。我们研究了SE后最初几天的生化事件。采用穿孔路径刺激诱导成年大鼠自我维持边缘SE，并允许动物恢复。在SE后16、44 h和8天进行生化研究，使用分光光度酶测定和高效液相色谱对局部脑匀浆进行分析，并与假手术对照组进行比较。在每个时间点进行血红素和伊红组织学检查。脑乌头酶和α -酮戊二酸脱氢酶（α kdh）活性在发病后16 ~ 44 h内均显著降低约20% (P < 0.05)， 8 d后恢复正常。这些酶是线粒体基质中三羧酸（Krebbs）循环的一部分，并且已知对自由基，特别是过氧亚硝酸盐损伤敏感。减少的谷胱甘肽水平也有类似的下降。组织学研究证实急性神经元损伤可达44小时，神经元丧失可达8天。这是SE后线粒体功能障碍和脑谷胱甘肽损失模式的首次体内证明。异常的模式与兴奋性毒性细胞损伤的可逆机制一致。这与变化的时机一起，为治疗干预提供了新的途径。(C) 2002 Elsevier Science B.V.版权所有
Status epilepticus (SE) in humans and animal models results in significant cerebral damage and an increased risk of subsequent seizures, associated with a characteristic pattern of neuronal loss particularly affecting the hippocampus. Seizure related cell death is considered to be excitotoxic, but studies have been limited, concentrating on terminal events rather than initial mechanisms. We have studied the biochemical events in the first few days following SE. Self-sustaining limbic SE was induced in adult rats using perforant path stimulation, and animals were allowed to recover. Biochemical studies were performed at 16, 44 h and 8 days following SE, using spectrophotometric enzyme assays and HPLC on regional brain homogenates compared with those from sham-operated controls. Haematoxylin and eosin histology was also undertaken at each time point. Brain aconitase and alpha-ketoglutarate dehydrogenase (alphaKDH) activity were both significantly (P < 0.05) reduced by approximately 20% in the first 16-44 h following status, but had returned to normal by 8 days. These enzymes are part of the tri-carboxylic acid (Krebbs) cycle in the mitochondrial matrix, and are known to be sensitive to free radical, especially peroxynitrite damage. There was a similar decrease in reduced glutathione levels. Histological studies confirmed evidence of acute neuronal damage up to 44 h, and neuronal loss by 8 days. This is the first in vivo demonstration of this pattern of mitochondrial dysfunction and loss of brain glutathione following SE. The pattern of abnormalities is consistent with reversible mechanisms being involved in excitotoxic cell damage. This, together with the timing of changes, suggests new avenues for therapeutic intervention. (C) 2002 Elsevier Science B.V. All rights reserved.