Blood level of brain-derived neurotrophic factor mRNA is progressively reduced in rodent models of Huntington's disease: Restoration by the neuroprotective compound CEP-1347
Blood level of brain-derived neurotrophic factor mRNA is progressively reduced in rodent models of Huntington's disease: Restoration by the neuroprotective compound CEP-1347
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DOI：
10.1016/j.mcn.2008.04.012
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发表时间：
2008-09-01
影响因子：
3.5
通讯作者：
Cattaneo, Elena
中科院分区：
文献类型：
--
作者：
Conforti, Paola;Ramos, Catarina;Cattaneo, Elena
亨廷顿氏病（HD）是一种年龄相关的神经退行性疾病，目前无法治疗。HD病理学的一个突出特征是促存活神经营养因子脑源性神经营养因子（BDNF）的减少。在几种HD啮齿动物模型和人类HD患者的大脑中，脑源性神经营养因子的mRNA和蛋白质水平均下降。我们现在第一次报告这种分子事件反映在HD啮齿动物模型的血液中。虽然在小鼠血液中无法检测到BDNF的蛋白水平，但在转基因小鼠（R6/2）和HD大鼠模型中，mRNA水平是可测量的，并且在HD进展期间减少。在八种不同的BDNF转录物中，只有BDNF外显子III在小鼠血液中转录，并且其表达在R6/2小鼠中相对于年龄匹配的野生型逐渐受损。HD大鼠血液中BDNF mRNA的评估显示了类似的结果，这是由神经营养因子的蛋白水平在症状阶段也显著降低的证据所加强的。最后，我们证明，急性和慢性治疗的R6/2小鼠与CEP-1347，混合谱系激酶（MLK）抑制剂与神经保护和神经营养作用，导致增加总BDNF mRNA在血液中相比，未经处理的R6/2小鼠。我们的研究结果表明，外周血中BDNF mRNA水平的改变是一个容易获得的测量疾病进展和药物疗效的HD啮齿动物模型。(C)2008年爱思唯尔公司All rights reserved.
Huntington's disease (HD) is an age-related neurodegenerative disorder that is currently untreatable. A prominent feature of HD pathology is the reduction of the pro-survival neurotrophin Brain-Derived Neurotrophic Factor (BDNF). Both mRNA and protein levels of BDNF are decreased in the brains of several HD rodent models and in human HD patients. We now report for the first time that this molecular event is mirrored in blood from HD rodent models. While protein levels of BDNF are undetectable in mouse blood, mRNA levels are measurable and diminish during HD progression in transgenic mouse (R6/2) and rat models of HD. Among the eight different BDNF transcripts, only BDNF exon III is transcribed in mouse blood and its expression is progressively compromised in R6/2 mice with respect to age-matched wild-types. Assessment of BDNF mRNA in HD rat blood shows a similar result, which is reinforced by evidence that protein levels of the neurotrophin are also significantly reduced at a symptomatic stage. Finally, we demonstrate that acute and chronic treatment of R6/2 mice with CEP-1347, a mixed lineage kinase (MLK) inhibitor with neuroprotective and neurotrophic effects, leads to increased total BDNF mRNA in blood when compared to untreated R6/2 mice. Our results indicate that alterations in BDNF mRNA levels in peripheral blood are a readily accessible measurement of disease progression and drug efficacy in HD rodent models. (C) 2008 Elsevier Inc. All rights reserved.