Inhibition by R(+) or S(-) pramipexole of caspase activation and cell death induced by methylpyridinium ion or beta amyloid peptide in SH-SY5Y neuroblastoma
Inhibition by R(+) or S(-) pramipexole of caspase activation and cell death induced by methylpyridinium ion or beta amyloid peptide in SH-SY5Y neuroblastoma
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DOI：
10.1002/jnr.10127
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发表时间：
2002-02-15
影响因子：
4.2
通讯作者：
Bennett, JP
中科院分区：
文献类型：
--
作者：
Abramova, NA;Cassarino, DS;Bennett, JP
神经退行性疾病（NDD）的细胞模型可以涉及与疾病的孟德尔形式相关的突变核基因的表达或被认为复制基本疾病特征的毒素的作用。通过将神经细胞暴露于甲基吡啶离子（MPP+）或神经毒性β淀粉样蛋白（BA）肽而产生的死亡经常用于分别研究帕金森病（PD）和阿尔茨海默病（AD）的散发性、最普遍形式的特征。我们研究了在复制SH-SY 5 Y人神经母细胞瘤细胞中细胞色素C释放到细胞质中，半胱天冬酶9和3的激活，以及钙黄绿素滞留的损失作为细胞死亡的“线粒体”途径的标志。暴露于5 mM MPP+（其在18-24小时内诱导凋亡性细胞死亡），在4小时内释放细胞色素C，激活半胱天冬酶9和3，并减少钙黄绿素积累。BA 25-35肽产生更快和更大的caspase 3活性升高;无毒BA 35-25反向序列没有观察到影响。线粒体过渡孔（MTP）的MPP+诱导的caspase激活的活性的依赖证明了通过预孵育与bongkreckic酸，它阻止了caspase 9和3的升高。普拉克索（PPX）的立体异构体是一种自由基清除剂和MTP开放抑制剂，可抑制半胱天冬酶活化（MPP+和BA）并恢复钙黄绿素蓄积（MPP+）。我们的研究结果表明，MPP和BA可以诱导细胞死亡，通过MTP依赖的激活caspase级联反应。PPX立体异构体干扰这些细胞死亡途径的活化，并且可以在临床上用作PD和AD以及相关疾病的神经保护剂。(C)2001 Wiley-Liss，Inc.
Cell models of neurodegenerative diseases (NDD) can involve expression of mutant nuclear genes associated with Mendelian forms of the diseases or effects of toxins believed to replicate essential disease features. Death produced by exposing neural cells to methylpyridinium ion (MPP+) or neurotoxic beta amyloid (BA) peptides is frequently used to study features of the sporadic, most prevalent forms of Parkinson's disease (PD) and Alzheimer's disease (AD), respectively. We examined in replicating SH-SY5Y human neuroblastoma cells the release of cytochrome C into cytoplasm, activation of caspases 9 and 3, and loss of calcein retention as markers of the "mitochondrial" pathway of cell death. Exposure to 5 mM MPP+, which induces apoptotic cell death within 18-24 hr, released cytochrome C within 4 hr, activated caspases 9 and 3, and reduced calcein accumulation. BA 25-35 peptide produced more rapid and greater elevations of caspase 3 activity; no effects were observed with the nontoxic BA 35-25 reverse sequence. The dependence on mitochondrial transition pore (MTP) activity of MPP+-induced caspase activations was demonstrated by preincubation with bongkreckic acid, which blocked elevations of caspases 9 and 3. Stereoisomers of pramipexole (PPX), a free radical scavenger and inhibitor of MTP opening, inhibited caspase activation (MPP+ and BA) and restored calcein accumulation (MPP+). Our results demonstrate that MPP and BA can induce cell death through MTP-dependent activation of caspase cascades. PPX stereoisomers interfere with activation of these cell death pathways and may be useful clinically as neuroprotectants in PD and AD and related diseases. (C) 2001 Wiley-Liss, Inc.