Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse.
Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse.
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DOI：
10.1016/j.trci.2017.12.001
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发表时间：
2018
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影响因子：
--
通讯作者：
Maccecchini ML
中科院分区：
文献类型：
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作者：
Teich AF;Sharma E;Barnwell E;Zhang H;Staniszewski A;Utsuki T;Padmaraju V;Mazell C;Tzekou A;Sambamurti K;Arancio O;Maccecchini ML
Posiphen对淀粉样前体蛋白（APP）的翻译抑制已被证明可以减少细胞培养物、动物模型和轻度认知障碍患者中的APP及其片段，使其成为治疗阿尔茨海默病的有希望的候选药物。我们使用阿尔茨海默病（APP/早老素-1）的小鼠模型来检查Posiphen的疗效，药效学和药代动力学。Posiphen治疗使APP/早老素-1小鼠的空间工作记忆、情境恐惧学习和突触功能的损伤正常化，而不影响其视力、运动技能或动机，也不影响野生型小鼠。Posiphen在最后一次给药后至少9小时内对减少APP和所有相关肽具有延长作用。其在脑中的浓度高于血浆，最丰富的代谢物是N8-norPosiphen。这是第一项证明在阿尔茨海默病模型中抑制APP及其片段翻译的治疗效果的研究。
Translational inhibition of amyloid precursor protein (APP) by Posiphen has been shown to reduce APP and its fragments in cell culture, animal models, and mildly cognitively impaired patients, making it a promising drug candidate for the treatment of Alzheimer's disease. We used a mouse model of Alzheimer's disease (APP/presenilin-1) to examine Posiphen's efficacy, pharmacodynamics, and pharmacokinetics. Posiphen treatment normalized impairments in spatial working memory, contextual fear learning, and synaptic function in APP/presenilin-1 mice, without affecting their visual acuity, motor skills, or motivation and without affecting wild-type mice. Posiphen had a prolonged effect in reducing APP and all related peptides for at least 9 hours after the last dose. Its concentration was higher in the brain than in plasma, and the most abundant metabolite was N8-norPosiphen. This is the first study demonstrating the therapeutic efficacy of inhibiting the translation of APP and its fragments in an Alzheimer's disease model.