Clapcote Steven J
School of Biomedical Sciences, University of Leeds, Leeds, LS2 9JT, UK.
Adv Neurobiol. 2017;17:103-131. doi: 10.1007/978-3-319-58811-7_5.
People in modern, affluent societies are living longer but also becoming increasingly overweight. With increased life expectancy comes increased risk of developing age-related cognitive decline and neurodegenerative diseases, such that an increasing proportion of life may be lived with cognitive impairment as age increases. Obesity is associated with poorer cognitive function in elderly subjects, and often leads to ill-health arising from various complications such as metabolic syndrome and type-2 diabetes mellitus. This chapter provides an overview of the effects of administering pan-phosphodiesterase-4 (PDE4) inhibitors to animal models of cognitive ageing, Alzheimer's disease, frontotemporal dementia, fragile X syndrome, obesity and diabetes. Inhibition of the PDE4B subtype specifically is discussed as an approach to avoid the emetic side effects of pan-PDE4 inhibitors, whilst retaining their therapeutic effects. Finally, the findings of rodent studies that employ genetic and pharmacological approaches to specifically target PDE4B are discussed in relation to the potential utility of PDE4B-selective inhibitors for the treatment of cognitive impairment and obesity-related metabolic diseases.
现代富裕社会中的人们寿命越来越长，但体重也越来越超标。随着预期寿命的增加，患与年龄相关的认知衰退和神经退行性疾病的风险也在增加，以至于随着年龄的增长，越来越多的人可能在认知障碍中度过余生。肥胖与老年受试者较差的认知功能有关，并且常常导致由各种并发症（如代谢综合征和2型糖尿病）引起的健康问题。本章概述了给予泛磷酸二酯酶-4（PDE4）抑制剂对认知衰老、阿尔茨海默病、额颞叶痴呆、脆性X综合征、肥胖和糖尿病动物模型的影响。特别讨论了特异性抑制PDE4B亚型作为一种避免泛PDE4抑制剂催吐副作用同时保留其治疗效果的方法。最后，结合PDE4B选择性抑制剂治疗认知障碍和肥胖相关代谢疾病的潜在效用，讨论了采用遗传和药理学方法特异性靶向PDE4B的啮齿动物研究结果。
