Searching for disease modifiers-PKC activation and HDAC inhibition - a dual drug approach to Alzheimer's disease that decreases Abeta production while blocking oxidative stress.
Searching for disease modifiers-PKC activation and HDAC inhibition - a dual drug approach to Alzheimer's disease that decreases Abeta production while blocking oxidative stress.
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DOI：
10.1002/cmdc.200900045
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发表时间：
2009-07
期刊：
影响因子：
3.4
通讯作者：
Langley, Brett
中科院分区：
文献类型：
--
作者：
Kozikowski, Alan P.;Chen, Yihua;Subhasish, Tapadar;Lewin, Nancy E.;Blumberg, Peter M.;Zhong, Zhenyu;D'Annibale, Melissa A.;Wang, Weng-Long;Shen, Yong;Langley, Brett
阿尔茨海默氏病（AD）是一种被充分研究的过程，其特征在于淀粉样蛋白斑块和神经元缠结的存在。在这项研究中，一系列的蛋白激酶C（PKC）激活剂进行了研究，其中一些也表现出组蛋白脱乙酰酶（HDAC）的抑制活性，在这样的假设下，这些化合物可能会提供一个新的途径，在发现用于治疗AD的药物。这些药物的PKC激活特性预计将增强淀粉样前体蛋白（APP）加工中的α-分泌酶途径，而其HDAC抑制预计将赋予神经保护活性。我们发现，苯并内酰胺类化合物9和11-14导致sAPPα的浓度依赖性增加和β-淀粉样蛋白（Aβ）产生的减少，使用这些药物的浓度范围为0.1 - 10 μM，与APP代谢向α-分泌酶加工途径的转变一致。此外，9-14在氧化应激的同型半胱氨酸（HCA）皮质神经元模型中在10至20 μM范围内显示出神经保护作用。与此同时，我们发现最具神经保护作用的化合物引起组蛋白乙酰化（H4）水平的增加，从而表明它们可能具有抑制组蛋白去乙酰化酶活性的能力。由于所研究的大多数化合物也显示出对PKC的纳摩尔结合亲和力，因此我们得出结论，有可能从头设计联合收割机将PKC激活特性沿着的试剂，从而产生能够调节淀粉样蛋白加工同时显示出神经保护的试剂。这些发现可能提供一种新的治疗方法，在治疗AD时表现出疾病修饰作用，而不是症状缓解。
Alzheimer's disease (AD) is a well-studied process characterized by the presence of amyloid plaques and neurofibrillary tangles. In this study, a series of protein kinase C (PKC) activators were investigated, some of which also exhibit histone deacetylases (HDACs) inhibitory activity, under the hypothesis that such compounds might provide a new path forward in the discovery of drugs for the treatment of AD. The PKC activating properties of these drugs were expected to enhance the α-secretase pathway in the processing of amyloid precursor protein (APP), while their HDAC inhibition was anticipated to confer neuroprotective activity. We found that the benzolactams compounds 9 and 11-14 caused a concentration-dependent increase in sAPPα and decrease in β-amyloid (Aβ) production using concentrations of these drugs in the range of 0.1∼10 μM, consistent with a shift of APP metabolism towards the α-secretase-processing pathway. Moreover, 9-14 showed neuroprotective effects in the 10 to 20 μM range in the homocysteate (HCA) cortical neuron model of oxidative stress. In parallel, we found that the most neuroprotective compounds caused increased levels of histone acetylation (H4), thus indicating their likely ability to inhibit histone deacetylase activity. As the majority of the compounds studied also show nanomolar binding affinities for PKC, we conclude that it is possible to design, de novo, agents that combine both PKC activating properties along with HDAC inhibitory properties, thereby resulting in agents capable of modulating amyloid processing while showing neuroprotection. These findings may offer a new approach to therapies that exhibit disease-modifying effects, as opposed to symptomatic relief, in the treatment of AD.
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影响因子：
4.7
作者：
Ding H;Dolan PJ;Johnson GV
通讯作者：
Johnson GV
影响因子：
7.3
作者：
Kozikowski, AP;Nowak, I;Blumberg, PM
通讯作者：
Blumberg, PM
影响因子：
4.8
作者：
Buxbaum, JD;Liu, KN;Black, RA
通讯作者：
Black, RA
影响因子：
64.8
作者：
Finnin, MS;Donigian, JR;Pavletich, NP
通讯作者：
Pavletich, NP
DOI：
10.1006/bbrc.2000.3000
发表时间：
2000-07-05
影响因子：
3.1
作者：
Frye, RA
通讯作者：
Frye, RA