Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer's Disease.
Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer's Disease.
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DOI：
10.1155/2018/2010675
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发表时间：
2018
期刊：
影响因子：
2.9
通讯作者：
Amin R
中科院分区：
文献类型：
--
作者：
Govindarajulu M;Pinky PD;Bloemer J;Ghanei N;Suppiramaniam V;Amin R
阿尔茨海默病（Alzheimer's disease，AD）是一种以蛋白质异常积累、突触功能障碍和认知障碍为特征的慢性神经退行性疾病。AD发病率和死亡率的不断增加表明迫切需要建立新的治疗潜力的分子靶点。过氧化物酶体增殖物激活受体γ（PPARγ）激动剂（如罗格列酮和吡格列酮）可减少淀粉样蛋白和tau蛋白病理，抑制神经炎症，并改善几种啮齿动物模型和轻度至中度AD患者的记忆障碍。然而，这些激动剂显示出差的血脑屏障渗透性，导致在脑中的生物利用度不足，因此需要在长期时间范围内的高剂量。此外，这些剂量水平与几种不良反应相关，包括体重增加、肝脏异常和心力衰竭的发生率增加。因此，需要鉴定新的化合物，其在脑中更选择性地靶向PPARγ，并且可以提供治疗益处而没有高的不良反应发生率。本文综述了PPARγ激动剂对AD各种病理的影响，重点介绍了新型选择性PPARγ调节剂的研究进展。
Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARγ more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARγ agonists influence various pathologies in AD with emphasis on development of novel selective PPARγ modulators.
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