Peroxisome proliferator-activated receptors γ/mitochondrial uncoupling protein 2 signaling protects against seizure-induced neuronal cell death in the hippocampus following experimental status epilepticus.
Peroxisome proliferator-activated receptors γ/mitochondrial uncoupling protein 2 signaling protects against seizure-induced neuronal cell death in the hippocampus following experimental status epilepticus.
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DOI：
10.1186/1742-2094-9-184
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发表时间：
2012-07-31
影响因子：
9.3
通讯作者：
Chan SH
中科院分区：
文献类型：
--
作者：
Chuang YC;Lin TK;Huang HY;Chang WN;Liou CW;Chen SD;Chang AY;Chan SH
癫痫持续状态引起亚细胞改变，可能导致海马神经细胞死亡。然而，癫痫发作诱导神经细胞死亡的机制尚不清楚。线粒体解偶联蛋白2(UCP2)在大脑的特定区域表达，在许多神经疾病中作为一种内源性神经保护分子出现。我们评价了UCP2在实验性癫痫持续状态下对癫痫诱导的海马神经细胞死亡的神经保护作用。在SD大鼠一侧海马CA3区微量注射海人酸(KA)，诱导双侧长时间癫痫发作。观察KA致痫后大鼠海马CA3区氧化蛋白水平、Bcl2、Bax和细胞色素c在胞浆和线粒体之间的移位，以及过氧化体增殖物激活受体γ(PPARγ)和UCP2的表达。观察双侧CA3区微量注射PPARγ激动剂罗格列酮或PPARγ拮抗剂GW9662对UCP2表达、超氧阴离子(O2·-)产生、氧化蛋白水平、线粒体呼吸链酶活性、Bcl2、Bax和细胞色素c移位的影响以及对双侧CA3区DNA断裂的影响。癫痫持续状态3~48 h后，海马CA3区氧化蛋白增多，Bax或细胞色素c的线粒体或胞浆移位。KA致痫持续状态后12~48 ，PPAR、UCP2表达增加。罗格列酮可使CA3亚区UCP2表达增加，蛋白氧化减少，O2·-产生减少，线粒体复合体功能障碍，抑制Bax和细胞色素c的转位，减少DNA片段化。GW9662预处理则产生相反的作用。PPARγ的激活上调了线粒体UCP2的表达，从而减少了活性氧的过量产生，改善了线粒体复合体I的功能障碍，抑制了线粒体bax的易位，并通过稳定线粒体跨膜电位，阻止了细胞色素c的释放，从而改善了癫痫持续状态后海马神经细胞的凋亡。
Status epilepticus induces subcellular changes that may lead to neuronal cell death in the hippocampus. However, the mechanism of seizure-induced neuronal cell death remains unclear. The mitochondrial uncoupling protein 2 (UCP2) is expressed in selected regions of the brain and is emerged as an endogenous neuroprotective molecule in many neurological disorders. We evaluated the neuroprotective role of UCP2 against seizure-induced hippocampal neuronal cell death under experimental status epilepticus. In Sprague–Dawley rats, kainic acid (KA) was microinjected unilaterally into the hippocampal CA3 subfield to induce prolonged bilateral seizure activity. Oxidized protein level, translocation of Bcl-2, Bax and cytochrome c between cytosol and mitochondria, and expression of peroxisome proliferator-activated receptors γ (PPARγ) and UCP2 were examined in the hippocampal CA3 subfield following KA-induced status epilepticus. The effects of microinjection bilaterally into CA3 area of a PPARγ agonist, rosiglitazone or a PPARγ antagonist, GW9662 on UCP2 expression, induced superoxide anion (O2· -) production, oxidized protein level, mitochondrial respiratory chain enzyme activities, translocation of Bcl-2, Bax and cytochrome c, and DNA fragmentation in bilateral CA3 subfields were examined. Increased oxidized proteins and mitochondrial or cytosol translocation of Bax or cytochrome c in the hippocampal CA3 subfield was observed 3–48 h after experimental status epilepticus. Expression of PPARγ and UCP2 increased 12–48 h after KA-induced status epilepticus. Pretreatment with rosiglitazone increased UCP2 expression, reduced protein oxidation, O2· - overproduction and dysfunction of mitochondrial Complex I, hindered the translocation of Bax and cytochrome c, and reduced DNA fragmentation in the CA3 subfield. Pretreatment with GW9662 produced opposite effects. Activation of PPARγ upregulated mitochondrial UCP2 expression, which decreased overproduction of reactive oxygen species, improved mitochondrial Complex I dysfunction, inhibited mitochondrial translocation of Bax and prevented cytosolic release of cytochrome c by stabilizing the mitochondrial transmembrane potential, leading to amelioration of apoptotic neuronal cell death in the hippocampus following status epilepticus.
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影响因子：
10.6
作者：
Carreras, Maria C.;Franco, Maria C.;Poderoso, Juan J.
通讯作者：
Poderoso, Juan J.
影响因子：
2.2
作者：
Cock, HR;Tong, X;Walker, MC
通讯作者：
Walker, MC
DOI：
10.1073/pnas.92.16.7162
发表时间：
1995-08-01
影响因子：
11.1
作者：
BONFOCO, E;KRAINC, D;LIPTON, SA
通讯作者：
LIPTON, SA
影响因子：
20.1
作者：
Chan, Samuel H. H.;Wu, Chiung-Ai;Chan, Julie Y. H.
通讯作者：
Chan, Julie Y. H.
影响因子：
3.4
作者：
Bernardo, A;Levi, G;Minghetti, L
通讯作者：
Minghetti, L