Cyclic Nucleotide Phosphodiesterase-4D(PDE4D) Subtype as A Potential Target for Treatment of Cognitive Deficits Associated with Alzheimer's Disease

作     者：James M.O’Donnell 

作者机构：Department of Pharmaceutical SciencesSchool of Pharmacy and Pharmaceutical SciencesUniversity at BuffaloThe State University of New York 

出 版 物：《神经药理学报》 (Acta Neuropharmacologica)

年 卷 期：2019年第Z1期

页      面：3-4页

学科分类：1002[医学-临床医学] 100203[医学-老年医学] 10[医学] 

主　　题：Alzheimer PDE4D Cyclic Nucleotide Phosphodiesterase-4D Subtype as A Potential Target for Treatment of Cognitive Deficits Associated with Alzheimer’s Disease Target 

摘      要：Considerable preclinical and clinical evidence suggests that inhibitors of PDE4 have effects on central nervous system function and behavior consistent with therapeutic utility for treating disorders such as memory loss and dementia. Despite this promise,dose-limiting side effects such as nausea and emesis has slowed drug development. Limiting drug action to specific PDE4 subtypes(i.e.,PDE4 A,B,C,and D) offers a means to produce therapeutic effects while minimizing side effects. However,the highly conserved catalytic site,to which classical PDE4 inhibitors bind,has limited the discovery of subtype-selective inhibitors. Recent drug discovery research showed that allosteric inhibitors,which do not bind to the catalytic site,can demonstrate subtype selectivity. Our study investigated the effects of an allosteric inhibitor of PDE4 D,BPN14770,on memory impairment induced by bilateral microinjection of Aβ 1-42 into the hippocampus of humanized PDE4 D(hPDE4 D) mice. Humanized PDE4 D mice provide a unique and powerful genetic tool for assessing PDE4 D target engagement. Behavioral studies showed that treatment with BPN14770 significantly improved memory acquisition and retrieval in the Morris water maze test and the percentage of alternations in the Y-maze test in the Aβ-impairment model. Microinjection of Aβ caused decreases the number of dendrites,dendritic length,and spine density of pyramidal neurons in the hippocampus. These changes were prevented by BPN14770. Molecular studies showed that BPN14770 reversed Aβ-induced decreases in synaptophysin,PSD-95,pCREB/CREB,BDNF,and VGF in the hippocampus. These results provide additional preclinical support for the utility of BPN14770 for the treatment of cognitive deficits in patients with Alzheimer’s disease.