Chuang Yao-Chung, Chen Shang-Der, Liou Chia-Wei, Lin Tsu-Kung, Chang Wen-Neng, Chan Samuel H H, Chang Alice Y W
Department of Neurology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan, Republic of China.
Epilepsia. 2009 Apr;50(4):731-46. doi: 10.1111/j.1528-1167.2008.01778.x. Epub 2008 Oct 30.
One cellular consequence of status epilepticus is apoptosis in the hippocampal CA3 subfield. We evaluated the hypothesis that the repertoire of cellular events that underlie such elicited cell death entails mitochondrial dysfunction induced by an excessive production of nitric oxide synthase II (NOS II)-derived NO, increased superoxide anion (O(2)(-)) production, and peroxynitrite formation.
In Sprague-Dawley rats, kainic acid was microinjected unilaterally into the hippocampal CA3 subfield to induce bilateral seizure-like electroencephalography (EEG) activity. The effects of pretreatments with various test agents on the induced O(2)(-) production, peroxynitrite formation, mitochondrial respiratory chain enzyme activities, cytochrome c/caspase-3 signaling, and DNA fragmentation in bilateral CA3 subfields were examined.
Significantly and temporally correlated increase in O(2)(-) and peroxynitrite levels (3 to 24 h), depressed mitochondrial Complex I activity (3 h), enhanced translocation of cytochrome c to cytosol (day 1), and augmented activated caspase-3 (day 7) and DNA fragmentation (day 7) were detected bilaterally in hippocampal CA3 subfields after the elicitation of sustained seizure. Pretreatment with microinjection into the bilateral hippocampal CA3 subfield of a water-soluble formulation of coenzyme Q(10); a selective NOS II inhibitor, S-methylisothiourea; a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl; an active peroxynitrite decomposition catalyst, 5,10, 15,20-tetrakis-(N-methyl-4-pyridyl)- porphyrinato iron (III); or a peroxynitrite scavenger, L-cysteine significantly blunted these cellular events.
Prolonged seizures prompted NO-, O(2)(-)-, and peroxynitrite-dependent reduction in mitochondrial respiratory enzyme Complex I activity, leading to cytochrome c/caspase-3-dependent apoptotic cell death in the hippocampal CA3 subfield after induction of experimental temporal lobe status epilepticus.
癫痫持续状态的一个细胞后果是海马CA3亚区的细胞凋亡。我们评估了这样一种假说，即引发这种细胞死亡的一系列细胞事件包括一氧化氮合酶II（NOS II）衍生的NO过量产生所诱导的线粒体功能障碍、超氧阴离子（O₂⁻）生成增加以及过氧亚硝酸盐的形成。
在Sprague-Dawley大鼠中，将海藻酸单侧微量注射到海马CA3亚区以诱导双侧癫痫样脑电图（EEG）活动。检测了用各种受试药物预处理对诱导的双侧CA3亚区O₂⁻生成、过氧亚硝酸盐形成、线粒体呼吸链酶活性、细胞色素c/半胱天冬酶-3信号传导以及DNA片段化的影响。
在诱发持续癫痫后，双侧海马CA3亚区检测到O₂⁻和过氧亚硝酸盐水平显著且在时间上相关的增加（3至24小时）、线粒体复合体I活性降低（3小时）、细胞色素c向胞质溶胶的易位增强（第1天）以及活化的半胱天冬酶-3增加（第7天）和DNA片段化增加（第7天）。向双侧海马CA3亚区微量注射辅酶Q₁₀的水溶性制剂、一种选择性NOS II抑制剂S-甲基异硫脲、一种超氧化物歧化酶模拟物4-羟基-2,2,6,6-四甲基哌啶-1-氧基、一种活性过氧亚硝酸盐分解催化剂5,10,15,20-四（N-甲基-4-吡啶基）卟啉铁（III）或一种过氧亚硝酸盐清除剂L-半胱氨酸进行预处理，可显著减弱这些细胞事件。
长时间癫痫发作促使线粒体呼吸酶复合体I活性依赖于NO、O₂⁻和过氧亚硝酸盐而降低，导致在实验性颞叶癫痫持续状态诱导后海马CA3亚区发生细胞色素c/半胱天冬酶-3依赖性凋亡细胞死亡。
