Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

被引:218
作者
Garcia-Osta, Ana [1 ]
Cuadrado-Tejedor, Mar [1 ]
Garcia-Barroso, Carolina [1 ]
Oyarzabal, Julen [1 ]
Franco, Rafael [1 ]
机构
[1] CIMA, Div Neurosci, Mol & Cell Neuropharmacol Lab, Pamplona, Spain
来源
ACS CHEMICAL NEUROSCIENCE | 2012年 / 3卷 / 11期
关键词
Clinical trial; cGMP; mild cognitive impairment; pCREB; GSK3; PKG; p-tau; sildenafil; tadalafil; LONG-TERM POTENTIATION; OBJECT RECOGNITION MEMORY; INDUCED COGNITIVE DYSFUNCTION; PDE9 INHIBITOR PF-04447943; MESSENGER-RNA EXPRESSION; INDUCED CALCIUM-RELEASE; CYCLIC-GMP PATHWAY; PROTEIN-KINASE-A; RADIAL-ARM MAZE; LATE-PHASE LTP;
D O I
10.1021/cn3000907
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Alzheimer's disease (AD) is the most common form of dementia among the elderly. In AD patients, memory loss is accompanied by the formation of beta-amyloid plaques and the appearance of tau in a pathological form. Given the lack of effective treatments for AD, the development of new management strategies for these patients is critical. The continued failure to find effective therapies using molecules aimed at addressing the anti beta amyloid pathology has led researchers to focus on other non-annyloid-based approaches to restore memory function. Promising non-amyloid related candidate targets include phosphosdiesterases (PDEs), and indeed, Rolipram, a specific PDE4 inhibitor, was the first compound found to effectively restore cognitive deficits in animal models of AD. More recently, PDES inhibitors have also been shown to effectively memory function. Accordingly, inhibitors of other members of the PDE family may also improve memory performance in AD and non-AD animal models. Hence, in this review, we will-summarize the data supporting the use of PDE inhibitors as cognitive enhancers and we will discuss the possible mechanisms of action underlying these effects. We shall also adopt a medicinal chemistry perspective that leads us to propose the most promising PDE candidates on the basis of inhibitor selectivity, brain distribution, and mechanism of action.
引用
收藏
页码:832 / 844
页数:13
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