摘要
阿尔茨海默病(AD)由多种致病原因引起。不规则淀粉样蛋白-β(Aβ)被认为是影响AD的一个关键因素,该蛋白源于由分泌酶家族分泌的前提蛋白的酶分泌产物。1-(3’,4’-Dichloro-2-fluoro[1,1’-biphenyl]-4-yl)-环丙烷羧酸(CHF5074)是一种能够抑制Aβ在AD小鼠模型大脑中沉积的非甾体抗炎衍生品。促凋亡因子TRAIL已被报道能介导Aβ依赖性神经毒性。本文,通过分化的人神经细胞瘤细胞系SH-SY5Y的体外实验对由Aβ25-35-激发的TRAIL毒性的CHF5074的作用进行了评价。用梯度浓度的CHF5074(浓度范围:1nM-1uM)对细胞进行预处理1h,然后用Aβ 25-35 或者 TRAIL人工感染72小时。结果表明,CHF5074的治疗防止了SH-SY5Y细胞系的细胞凋亡,并具有浓度依赖性。其最大活性浓度为10 nM。然后,相关的潜在分子机制在CHF5074的保护作用的研究暗示了胱门蛋白酶以及各种酶,包括压力和MAP激酶的水平是由CHF5074所调控。最后,用CHF5074治疗的受伤的人神经母细胞瘤细胞系SH-SY5Y起到了显著的防护细胞凋亡的作用。这些数据的堆积表明CHF5074可用于在神经退行性疾病的神经保护治疗的潜在候选药物。
关键词: 阿尔茨海默病,神经性炎症,细胞因子的凋亡,治疗
Current Alzheimer Research
Title:CHF5074 Protects SH-SY5Y Human Neuronal-like Cells from Amyloidbeta 25-35 and Tumor Necrosis Factor Related Apoptosis Inducing Ligand Toxicity In Vitro
Volume: 11 Issue: 7
Author(s): Nicole Ronsisvalle, Giulia Di Benedetto, Carmela Parenti, Salvatore Amoroso, Renato Bernardini and Giuseppina Cantarella
Affiliation:
关键词: 阿尔茨海默病,神经性炎症,细胞因子的凋亡,治疗
摘要: Alzheimer’s disease (AD) is contributed by multiple pathogenic causes. The anomalous protein amyloid-β (Aβ) is regarded as a pivotal factor in AD, and originates from enzymatic cleavage of a precursor protein by the secretase family. 1-(3’,4’-Dichloro-2-fluoro[1,1’-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074) is a non-steroidal antiinflammatory derivative able to inhibit Aβ deposition in the brain of transgenic mouse models of AD. The proapoptotic cytokine TRAIL has been reported to mediate Aβ-dependent neurotoxicity. Here, the effects of CHF5074 on Aβ25-35- triggered TRAIL toxicity were evaluated in the differentiated human neuroblastoma cell line SH-SY5Y in vitro. Cells were pre-treated 1h with CHF5074 at graded concentrations (range: 1 nM-1uM) and then challenged for 72 h with either Aβ25-35 or TRAIL. Results show that CHF5074 treatment prevented apoptotic death in SH-SY5Y cell line in a concentration- dependent fashion. Its maximally active concentration was 10 nM. Then, investigation of related molecular mechanisms underlying such protective effect of CHF5074 suggested that the levels of caspases, as well as of various kinases, including stress and MAP kinases, are modulated by CHF5074. Finally, treatment of injured human neuroblastoma cell line SH-SY5Y with CHF5074 resulted in prominent protection from apoptotic death. The bulk of these data suggest that CHF5074 represents a potential candidate for pharmacological neuroprotective treatment in neurodegenerative disorders.
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Ronsisvalle Nicole, Di Benedetto Giulia, Parenti Carmela, Amoroso Salvatore, Bernardini Renato and Cantarella Giuseppina, CHF5074 Protects SH-SY5Y Human Neuronal-like Cells from Amyloidbeta 25-35 and Tumor Necrosis Factor Related Apoptosis Inducing Ligand Toxicity In Vitro, Current Alzheimer Research 2014; 11 (7) . https://dx.doi.org/10.2174/1567205011666140618104430
DOI https://dx.doi.org/10.2174/1567205011666140618104430 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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