Advances in phosphodiesterase （PDE） research： clinical potentials of PDE4 inhibitors in Alzheimer＇ s disease and alcoholism  

出　　处：《中国药理学通报》2015年第B11期269-270,共2页Chinese Pharmacological Bulletin

摘　　要：PDE is a supeffamily of enzymes that break down the important second messengers cyclic AMP （cAMP） PDE4 is the most important fami- and cyclic GMP （cGMP）. There are 11 PDE families （ PDEI-11 ） ; among them, ly in the control of intracellular cAMP signaling. It has been established that PDE4 is an essential player in the me- diation of AD and alcoholism. Chronic alcohol consumption can cause alcohol-related dementia and 50% - 75% of detoxified alcoholics have memory or cognition impairment. The lecture will focus on the unique role of PDE4 and its isoforms （PDE4A-D） in mediating AD and alcoholism and the cellular mechanisms involved. Specifically, using mice deficient in PDE4A, PDE4B, or PDE4D, and their wild type （WT） controls, it was found that PDE4Adeficiencydecreased alcohol intake and preference and reversed Abeta42-induced memory deficits. In con- trast, deficiency of PDE4B only mimicked the ability of PDE4A-deficiency to reduce alcohol consumption, while deficiency of PDE4D only reversed Abeta42-induced memory deficits. In addition, levels of cAMP and phospho- CREB （pCREB） were increased in the hippocampus of mice deficient in PDE4A or PDE4D, which also produced reversal of Abeta42-induced decreases in pCREB. These datasuggest that PDE4 isoforms have different roles in me-diating alcohol-drinking behavior and memoryin Alzheimer＇ s disease, which are mediated by cAMP/CREB signa- ling. The results indicate PDE4A as a potential new target for alcohol-related dementia, although studies with ani- mal models of alcohol-related dementia are needed to clarify this.

关 键 词：PDE4 老年痴呆症 磷酸二酯酶 酒精中毒 抑制剂 磷酸化CREB PCREB 记忆障碍 

分 类 号：R974[医药卫生—药品] R749.16[医药卫生—药学]