RNA therapeutics directed to the non coding regions of APP mRNA, in vivo anti-amyloid efficacy of paroxetine, erythromycin, and N-acetyl cysteine.
RNA therapeutics directed to the non coding regions of APP mRNA, in vivo anti-amyloid efficacy of paroxetine, erythromycin, and N-acetyl cysteine.
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DOI：
10.2174/156720506777632835
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发表时间：
2006-06
影响因子：
2.1
通讯作者：
S. Tucker;Michelle Ahl;Hyun-Hee Cho;S. Bandyopadhyay;G. Cuny;A. Bush;L. Goldstein;D. Westaway;Xudong Huang;J. Rogers
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文献类型：
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作者：
S. Tucker;Michelle Ahl;Hyun-Hee Cho;S. Bandyopadhyay;G. Cuny;A. Bush;L. Goldstein;D. Westaway;Xudong Huang;J. Rogers
针对淀粉样前体蛋白转录物的5'前导序列的前导化合物（即，帕罗西汀（SSRI）、N-乙酰半胱氨酸（抗氧化剂）和红霉素（大环内酯类抗生素））用于初步研究以评价它们在阿尔茨海默病（AD）的TgCRND 8转基因小鼠模型中的抗淀粉样蛋白功效。在小鼠暴露于帕罗西汀（N=5）、NAC（N=7）和红霉素（N=7）后，相对于匹配的安慰剂对应物，Abeta肽的相对水平降低。帕罗西汀限制APP全蛋白水平和总Abeta肽水平（通过定量蛋白质印迹和ELISA测定在两个单独的位点进行Abeta的测量）。帕罗西汀数据为我们进一步筛选APP 5 'UTR靶点以鉴定在体内表现出抗淀粉样蛋白功效的新药的策略提供了概念验证。红霉素和阿奇霉素是大环内酯类抗生素，可显著改变SH-SY 5 Y细胞中APP C-末端片段（CTF）的切割。经口给予TgCRND 8小鼠的红霉素持续（100%）降低脑Abeta（1-42）水平。这些数据表明帕罗西汀、NAC和红霉素具有高度统计学显著的抗淀粉样蛋白趋势。讨论了使用更大的TgCRND 8小鼠队列对这些化合物进行进一步研究的可能性，特别是因为红霉素最近已暴露于小鼠另外6个月（N=6）。将有可能采用帕罗西汀和红霉素的化学结构作为AD治疗药物设计和开发的起点。
Lead compounds directed to the 5' leader of the Amyloid Precursor Protein transcript (i.e., paroxetine (SSRI), N-acetyl cysteine (antioxidant), and erythromycin (macrolide antibiotic)) were employed in a pilot study to evaluate their anti-amyloid efficacy in the TgCRND8 transgenic mouse model for Alzheimer's Disease (AD). The relative levels of Abeta peptide were reduced after exposure of mice to paroxetine (N=5), NAC (N=7), and erythromycin (N=7) relative to matched placebo counterparts. Paroxetine limited the levels of APP holoprotein and total Abeta peptide levels (measurements of Abeta were performed at two separate sites by quantitative western blotting and ELISA assay). The paroxetine data provided proof-of-concept for our strategy for further screening the APP 5'UTR target to identify novel drugs that exhibit anti-amyloid efficacy in vivo. Erythromycin and azithromycin were macrolide antibiotics that markedly changed the cleavage of the APP C-Terminal Fragment (CTF) in SH-SY5Y cells. Erythromycin provided orally to TgCRND8 mice consistently (100%) reduced brain Abeta(1-42) levels. These data demonstrated a highly statistically significant anti-amyloid trend for paroxetine, NAC and erythromycin. The potential for conducting further studies with these compounds using larger cohorts of TgCRND8 mice is discussed, particularly since erythromycin has recently been exposed to mice for a further 6 months (N=6). It will be possible to employ the chemical structures of paroxetine and erythromycin as starting points for drug design and development for AD therapeutics.