Inhibition of cyclin-dependent kinases is neuroprotective in 1-methyl-4-phenylpyridinium-induced apoptosis in neurons
Inhibition of cyclin-dependent kinases is neuroprotective in 1-methyl-4-phenylpyridinium-induced apoptosis in neurons
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DOI：
10.1016/j.neuroscience.2007.01.042
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发表时间：
2007-04-25
期刊：
影响因子：
3.3
通讯作者：
Camins, A.
中科院分区：
文献类型：
--
作者：
Alvira, D.;Tajes, M.;Camins, A.
帕金森病神经元细胞死亡的生化途径尚未完全确定。线粒体功能障碍，特别是线粒体复合物I的改变，是帕金森病神经毒素1-甲基-4-苯基吡啶（MPP+）诱导神经元凋亡的主要靶点。在本研究中，我们研究的作用，半胱天冬酶依赖性和非依赖性途径MPP+诱导的大鼠小脑颗粒神经元（CGNs）的凋亡。我们发现MPP+处理CGN后细胞周期蛋白cyclin D、cyclin E、cdk 2、cdk 4和转录因子E2 F-1的表达明显增加。Flavopiridol（FLAV）是一种广泛的细胞周期蛋白依赖性激酶（CDKs）抑制剂，可减弱MPP+的神经毒性作用，并显著减弱MPP+ 200 μ M介导的细胞凋亡。同样地，抗氧化剂维生素E（vit E）增加神经元细胞活力并减弱MPP+诱导的细胞凋亡。此外，vit E还能抑制该毒素诱导的细胞周期蛋白D和E2 F-1的表达。由于广谱半胱天冬酶抑制剂zVAD-favorite没有减弱MPP+诱导的CGN细胞凋亡，我们的数据提供了一种不依赖半胱天冬酶的机制，该机制由细胞周期中的神经元重入和促凋亡转录因子乌法的表达增加介导。我们的研究结果还表明氧化应激在MPP+介导的细胞周期中的神经元重入中的潜在作用。最后，我们的数据进一步支持flavopiridol治疗帕金森病的治疗潜力。(C)2007年IBRO。由爱思唯尔有限公司出版。保留所有权利。
The biochemical pathways involved in neuronal cell death in Parkinson's disease are not completely characterized. Mitochondrial dysfunction, specifically alteration of the mitochondrial complex I, is the primary target of the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP+) induced apoptosis in neurons. In the present study, we examine the role of caspase-dependent and -independent routes in MPP+-induced apoptosis in rat cerebellar granule neurons (CGNs). We show a distinct increase in the expression of the cell cycle proteins cyclin D, cyclin E, cdk2, cdk4 and the transcription factor E2F-1 following a MPP+ treatment of CGNs. Flavopiridol (FLAV), a broad inhibitor of cyclin-dependent kinases (CDKs), attenuated the neurotoxic effects of MPP+ and significantly attenuates apoptosis mediated by MPP+ 200 mu M. Likewise, the antioxidant vitamin E (vit E) increases neuronal cell viability and attenuates apoptosis induced by MPP+. Moreover, the expression levels of cyclin D and E2F-1 induced by this parkinsonian neurotoxin were also attenuated by vit E. Since, the broad-spectrum caspase inhibitor zVAD-fmk did not attenuate MPP+-induced apoptosis in CGNs, our data provide a caspase-independent mechanism mediated by neuronal reentry in the cell cycle and increased expression of the pro-apoptotic transcription factor UFA. Our results also suggest a potential role of oxidative stress in neuronal reentry in the cell cycle mediated by MPP+. Finally, our data further support the therapeutic potential of flavopiridol, for the treatment of Parkinson's disease. (C) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.