Concomitant histone deacetylase and phosphodiesterase 5 inhibition synergistically prevents the disruption in synaptic plasticity and it reverses cognitive impairment in a mouse model of Alzheimer's disease.
Concomitant histone deacetylase and phosphodiesterase 5 inhibition synergistically prevents the disruption in synaptic plasticity and it reverses cognitive impairment in a mouse model of Alzheimer's disease.
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DOI：
10.1186/s13148-015-0142-9
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发表时间：
2015
影响因子：
5.7
通讯作者：
Garcia-Osta A
中科院分区：
文献类型：
--
作者：
Cuadrado-Tejedor M;Garcia-Barroso C;Sanzhez-Arias J;Mederos S;Rabal O;Ugarte A;Franco R;Pascual-Lucas M;Segura V;Perea G;Oyarzabal J;Garcia-Osta A
鉴于组蛋白乙酰化在记忆过程中的意义，组蛋白去乙酰化酶抑制剂（HDACIs）已被假定为阿尔茨海默病（AD）认知障碍的潜在调节剂。然而，在目前可用的广谱HDACI患者中描述了剂量依赖性副作用，这解释了为什么它们对慢性疾病的治疗潜力尚未实现。在这里，通过同时靶向两个独立的酶活性，组蛋白脱乙酰酶（HDAC）和磷酸二酯酶-5（PDE 5），我们提出了一种新的抑制作用模式，可能会增加HDACIs的治疗特异性。vorinostat（一种泛HDACI）和他达拉非（一种PDE 5抑制剂）的组合挽救了APP/PS1小鼠切片中受损的长时程增强。当体内给药时，这些药物的组合减轻了AD小鼠的认知缺陷以及淀粉样蛋白和tau病理学，并且逆转了海马神经元上树突棘密度的降低。值得注意的是，伏立诺他和他达拉非的联合治疗比单独使用每种药物更有效，无论是针对症状还是疾病改善，重要的是，这些作用在4周洗脱期后持续存在。结果突出了抑制HDAC和PDE 5的分子组合作为AD治疗的治疗方法的药理学潜力。本文的在线版本（doi：10.1186/s13148-015-0142-9）包含补充材料，可供授权用户使用。
Given the implication of histone acetylation in memory processes, histone deacetylase inhibitors (HDACIs) have been postulated as potential modulators of cognitive impairment in Alzheimer’s disease (AD). However, dose-dependent side effects have been described in patients with the currently available broad-spectrum HDACIs, explaining why their therapeutic potential has not been realized for chronic diseases. Here, by simultaneously targeting two independent enzyme activities, histone deacetylase (HDAC) and phosphodiesterase-5 (PDE5), we propose a novel mode of inhibitory action that might increase the therapeutic specificity of HDACIs. The combination of vorinostat, a pan-HDACI, and tadalafil, a PDE5 inhibitor, rescued the long-term potentiation impaired in slices from APP/PS1 mice. When administered in vivo, the combination of these drugs alleviated the cognitive deficits in AD mice, as well as the amyloid and tau pathology, and it reversed the reduced dendritic spine density on hippocampal neurons. Significantly, the combination of vorinostat and tadalafil was more effective than each drug alone, both against the symptoms and in terms of disease modification, and importantly, these effects persisted after a 4-week washout period. The results highlight the pharmacological potential of a combination of molecules that inhibit HDAC and PDE5 as a therapeutic approach for AD treatment. The online version of this article (doi:10.1186/s13148-015-0142-9) contains supplementary material, which is available to authorized users.