NP-12 The Phosphodiesterase-4 Inhibitor Roflumilast Reverses Cognition Deficits and Depression-Like Effects via cAMP Signaling-Mediated Neuroprotection in APP/PS1 Transgenic Mice
作者机构：Institute of PharmacologyTaishan Medical UniversityTai’an271016China Departments of Behavioral Medicine&Psychiatry and PhysiologyPharmacology&Neurosciencethe Rockefeller Neurosciences InstituteWest Virginia University Health Sciences CenterMorgantownWV 26506USA
出 版 物：《神经药理学报》 (Acta Neuropharmacologica)
年 卷 期：2018年第8卷第4期
页 面：110-111页
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：This work was supported by research grants from National Natural Science Foundation of China(81773717 to HTZ 81601229 and 81441111 to HW)
主 题：Alzheimer’s disease roflumilast PDE4 cAMP signaling APP/PS1 mice cognition depression
摘 要：Phosphodiesterase-4(PDE4)has been demonstrated to be a promising target for treatment of Alzheimer’s disease(AD).Roflumilast(Rof),a potent PDE4 inhibitor,has been approved for treatment of chronic obstructive pulmonary disease(COPD)in *** studies have shown that Rof improves cognition at doses that do not cause an emetic response,the major side-effect of PDE4 ***,the effect of Rof on cognition associated with AD remains largely *** we examined the effects of Rof on behavioral dysfunction and the related mechanisms in APP/PS1 double transgenic mice,a widely used model for *** at 10 months of age were first tested in novel object recognition for *** recognition index in APP/PS1 mice was decreased compared to WT mice,which was reversed by Rof at 5 and 10 mg·*** was then verified in the Morris water-maze *** escape latency during acquisition training was significantly longer and the entries into the target quadrant during the probe trial were much less compared to WT controls,these were also reversed by *** the tail-suspension and forced-swimming tests,which measure depression-like behavior,APP/PS1 mice showed prolonged immobility time,which was reversed by *** addition,the staining of HE and Nissl showed that Rof reduced the loss of neurons and neurocyte apoptosis in APP/PS1 *** also reversed the decreased ratio of Bcl-2/BAX and inhibited the increased expression of PDE4D in the cerebral cortex and hippocampus of APP/PS1 ***,Rof reversed the decreased levels of cAMP and expression of phosphorylated cAMP response element-binding protein(CREB)and brain derived neurotrophic factor(BDNF)in APP/PS1 ***,these results suggest that Rof not only improves learning and memory,but attenuates depression-like behavior in AD mice,likely via PDE4D/cAMP/CREB/BDNF signaling-mediated ***,Rof can be a therapeutic agent for AD,in particular the comorbidity of memory deficits and depres
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