在阿尔茨海默病小鼠模型中,低剂量饮食vorinostat增加脑组蛋白乙酰化水平并减少氧化应激。

IF 3.4 3区 医学 Q2 NEUROSCIENCES
Chhanda Bose, Ashly Hindle, Shane C Smith, Jake Strickland, Charlie Zhang, Isabel Guzman, Adam Baker, Igor Ponomarev, Maria Manczak, Andrew C Shin, Ranadip Pal, Sharda P Singh, J Josh Lawrence
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引用次数: 0

摘要

背景:阿尔茨海默病(AD)破坏组蛋白乙酰化/去乙酰化稳态,阻断转录因子进入DNA,影响学习。伏立诺他(Vorinostat, VOR)是fda批准的唯一具有口服生物利用性和脑渗透性的HDAC抑制剂,在AD模型中具有神经保护作用。我们在AD小鼠模型中通过饮食给予VOR,检查耐受性,并进行生化分析。我们的目的是研究饮食给药vorinostat的耐受性,包括组蛋白乙酰化、淀粉样蛋白-β (Aβ)产生、氧化应激(OS)、线粒体健康和突触完整性的变化。方法采用含对照、0.18 mg/g(低剂量)和0.36 mg/g(高剂量)VOR的食物微丸给药hAβ-KI AD小鼠14 d。Western blot检测脑乙酰组蛋白H3 (AH3)、总H3表达及突触标志物。测定脑组织Aβ、H2O2、抗氧化能力、脂质过氧化(通过4-羟基壬烯醛(4-HNE))、三磷酸腺苷(ATP)和柠檬酸合成酶(CS)活性。结果两种剂量的VOR均能抑制脑HDAC酶活性,提高AH3和H3的表达。Aβ和突触蛋白未受显著影响;然而,两种剂量下的OS标记均有改善。两种剂量均增加了CS活性,而ATP仅在低剂量时增加。最后,低剂量VOR可耐受2个月以上。结论:通过饮食给药的低剂量VOR在AD小鼠中是可耐受的,成功地抑制了脑HDAC活性,同时降低了OS并改善了线粒体健康。本研究改进了现有的临床前实验设计,通过饮食干预使组蛋白乙酰化无创操作成为可能。这种给药途径为未来的临床前动物研究提供了优势。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Low-dose dietary vorinostat increases brain histone acetylation levels and reduces oxidative stress in an Alzheimer's disease mouse model.

BackgroundAlzheimer's disease (AD) disrupts histone acetylation/deacetylation homeostasis, blocking access of transcription factors to DNA, and compromising learning. Vorinostat (VOR), the only FDA-approved HDAC inhibitor that is orally bioavailable and brain penetrant, confers neuroprotection in AD models. We delivered VOR via diet in an AD mouse model, examining tolerability, accompanied by biochemical analyses.ObjectiveOur objective was to examine dietary delivery of vorinostat for tolerability, including changes to histone acetylation, amyloid-β (Aβ) production, oxidative stress (OS), mitochondrial health, and synaptic integrity.MethodsFood pellets containing control, 0.18 mg/g (low-dose) and 0.36 mg/g (high-dose) VOR were administered to hAβ-KI AD mice for 14 days. Brain acetyl-histone H3 (AH3), total H3 expression, and synaptic markers were measured via Western blot. Aβ, H2O2, antioxidant capacity, lipid peroxidation (via 4-hydroxynonenal (4-HNE)), adenosine triphosphate (ATP), and citrate synthase (CS) activity were measured in brain tissue.ResultsVOR inhibited brain HDAC enzyme activity and increased AH3 and H3 expression at both VOR doses. Aβ and synaptic proteins were not significantly affected; however, OS markers were improved at both doses. Both doses increased CS activity, while ATP was increased only at the low dose. Finally, low-dose VOR was tolerable over 2 months.ConclusionsWe established that low-dose VOR, delivered via diet, is tolerable in AD mice, successfully inhibiting brain HDAC activity while reducing OS and improving mitochondrial health. This study improves existing preclinical experimental designs by enabling noninvasive manipulation of histone acetylation through dietary intervention. This route of administration provides advantages for future preclinical animal studies.

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来源期刊
Journal of Alzheimer's Disease
Journal of Alzheimer's Disease 医学-神经科学
CiteScore
6.40
自引率
7.50%
发文量
1327
审稿时长
2 months
期刊介绍: The Journal of Alzheimer''s Disease (JAD) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer''s disease. The journal publishes research reports, reviews, short communications, hypotheses, ethics reviews, book reviews, and letters-to-the-editor. The journal is dedicated to providing an open forum for original research that will expedite our fundamental understanding of Alzheimer''s disease.
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