S2A-5 Targeting PDE4 for Alzheimer’s Disease and Alcoholism:An implication in Alcohol-Related Dementia?  

作　　者：WANG Hao ZHANG Fang-fang FU Hua-rong ZHOU Yan-meng LIU Xin HOU Xue-qin HU Wei Rolf Hansen XU Ying James O’Donnell 张汉霆 ZHANG Han-ting

机构地区：[1]Institute of Pharmacology,the First Medical University of Shandong,Tai’an,271016,China [2]Departments of Behavioral Medicine&Psychiatry,Physiology&Pharmacology,and Neuroscience,the Rockefeller Neurosciences Institute,West Virginia University Health Sciences Center,Morgantown,WV 26506,USA [3]Department of Pharmaceutical Sciences,School of Pharmacy&Pharmaceutical Sciences,State University of New York at Buffalo,Buffalo,NY 14214,USA

出　　处：《神经药理学报》2018年第4期39-41,共3页Acta Neuropharmacologica

摘　　要：Background:Phosphodiesterase 4(PDE4),one of the 11 PDE enzyme families that hydrolyze cyclic nucleotides,is critical for controlling intracellular cyclic AMP(cAMP)concentrations and plays an important role in regulating alcohol consumption and mediating memory in dementia such as Alzheimer’s disease(AD).Chronic alcohol consumption can cause alcohol-related dementia and 50%~75%of detoxified alcoholics have memory or cognition impairment.However,the role of PDE4 and its mechanism remain to be characterized and elucidated.Methods:Using the water-maze,passive avoidance,or novel object recognition test,we examined the effects of rolipram,a prototypical PDE4 inhibitor,and roflumilast,a potent PDE4 inhibitor which has been approved for treatment of chronic obstructive pulmonary disease(COPD)in humans,on memory loss in APP/PS1 double transgenic mice,a widely used model for AD.In addition,we tested the effects of the PDE4 inhibitors,via ip,intra-gastric,or intrastriatum infusion,on ethanol intake and preference using the mouse two-bottle choice paradigm.Mice deficient in PDE4A,PDE4B,or PDE4D(4AKO,4BKO,and 4DKO,respectively)and their wild type(WT)controls were tested for ethanol consumption and memory;the latter was measured in the absence or presence of beta-amyloid peptide 1-42(Abeta42)infused into the dorsal hippocampus.Results:Similar to rolipram,roflumilast reversed memory deficits in APP/PS1 mice in all the memory tests and reduced ethanol intake and preference in C57BL/6 mice in two-bottle choice.Consistent with the results in the memory tests,roflumilast reduced the loss of neurons and neurocyte apoptosis in AD mice,as shown using HE and Nissl staining.It also reversed the decreased ratio of Bcl-2/BAX in the cerebral cortex and hippocampus of AD mice.In addition,roflumilast reversed the decreased levels of cAMP and expression of phosphorylated cAMP response element-binding protein(CREB)and brain derived neurotrophic factor(BDNF)in AD mice.Compared to the WT controls,4AKO mice displayed significant decreases in et

关 键 词：Phosphodiesterase-4(PDE4) Alzheimer’s disease(AD) ALCOHOLISM cAMP signaling memory trangenic mice 

分 类 号：TP311.56[自动化与计算机技术—计算机软件与理论]