Retinoid X Receptor Alpha Nitro-ligand Z-10 and Its Optimized Derivative Z-36 Reduce beta-Amyloid Plaques in Alzheimer's Disease Mouse Model
Retinoid X Receptor Alpha Nitro-ligand Z-10 and Its Optimized Derivative Z-36 Reduce beta-Amyloid Plaques in Alzheimer's Disease Mouse Model
复制标题
RXRalpha 硝基配体 Z-10 及其优化衍生物 Z-36 减少 AD 小鼠模型中的 β-淀粉样斑块。
DOI：
10.1021/acs.molpharmaceut.8b00096
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发表时间：
2019
影响因子：
4.9
通讯作者：
Zhou Hu
中科院分区：
文献类型：
--
作者：
Ren Gaoang;Bao Wei;Zeng Zhiping;Zhang Weidong;Shang Ce;Wang Maosi;Su Ying;Zhang Xiao kun;Zhou Hu
Bexarotene是类视黄醇X受体α (RXRα)的激动剂，已被证明通过激活RXR/LXR和RXR/PPAR异源二聚体来增加apoE， ABCA1和ABCG1的表达，导致阿尔茨海默病（AD）小鼠模型大脑中淀粉样蛋白β (Aβ)蛋白的清除和小鼠认知缺陷的逆转。硝基苯乙烯衍生物Z-10是RXRα的第一个硝基配体。我们假设Z-10及其衍生物具有与贝萨罗汀相似的作用。通过在萘环2位、4位分别引入甲氧基、羟基和甲氧基，合成了一系列Z-10衍生物。我们的报告基因实验表明，2位甲基和甲氧基取代基团的衍生物比相应的4取代衍生物更能激活Gal4-DBD/RXRα- lbd和RXRα同二聚体以及RXRα异二聚体。2位或4位羟基取代的衍生物均不能激活RXRα。RXRα活性越强的衍生物与RXRα的结合亲和力越高。Z-10及其2-乙氧基取代衍生物Z-36均能显著减少AD小鼠海马和皮质内的β斑块，其中Z-36的作用更强。这可能是由于Z-36比Z-10更能激活RXR/LXR和RXR/PPAR异源二聚体，诱导ABCA1和ABCG1的表达。由此可见，Z-10的2-位点比4-位点更能激活RXRα，而Z-36是Z-10在AD小鼠模型中减少β斑块的优化衍生物。
Bexarotene, an agonist of retinoid X receptor alpha (RXRα), has been shown to increase the expression of apoE, ABCA1, and ABCG1 by activating RXR/LXR and RXR/PPAR heterodimers, resulting in amyloid β (Aβ)-protein clearance in the brain of an Alzheimer’s disease (AD) mouse model and reversal of mouse cognitive deficits. Nitrostyrene derivative Z-10 is the first identified nitro-ligand of RXRα. We hypothesized that Z-10 and its derivatives have the similar effect as bexarotene. A series of Z-10 derivatives were synthesized by introducing methoxyl, hydroxyl, and methoxy groups in 2- or 4-position of naphthalene ring, respectively. Our reporter gene assays showed that the derivatives with substituted groups of methyl and methoxyl in position 2 were more potent to activate Gal4-DBD/RXRα-LBD and RXRα homodimer as well as RXRα heterodimers than the corresponding 4-substituted derivatives. The derivatives with hydroxyl substitution in either 2- or 4-position failed to activate RXRα. Consistently, the derivatives with stronger potency of RXRα activation had higher RXRα binding affinity. Z-10 and its 2-ethyoxyl substituted derivative Z-36 reduced Aβ plaques in both hippocampus and cortex of AD mouse model significantly, of which Z-36 had stronger efficacy. This may due to the stronger ability of Z-36 than Z-10 in activating RXR/LXR and RXR/PPAR heterodimers and inducing ABCA1 and ABCG1 expressions. Thus, the 2- rather than 4-position was the better site for Z-10 modification as to RXRα transactivation, and Z-36 is an optimized derivative of Z-10 as to reducing Aβ plaques in AD mouse model.