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：WANG Hao ZHANG Fang-fang XU Yong FU Hua-rong WANG Xiao-dan WANG Lei CHEN Wei XU Xiao-yan GAO Yong-feng ZHANG Ji-guo ZHANG Han-ting 

机构地区：[1]Institute of Pharmacology,Taishan Medical University,Tai’an,271016,China [2]Departments of Behavioral Medicine&Psychiatry and Physiology,Pharmacology&Neuroscience,the Rockefeller Neurosciences Institute,West Virginia University Health Sciences Center,Morgantown,WV 26506,USA

出　　处：《神经药理学报》2018年第4期110-111,共2页Acta Neuropharmacologica

基　　金：This work was supported by research grants from National Natural Science Foundation of China(81773717 to HTZ;81601229 and 81441111 to HW).

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 humans.Recent studies have shown that Rof improves cognition at doses that do not cause an emetic response,the major side-effect of PDE4 inhibitors.However,the effect of Rof on cognition associated with AD remains largely unknown.Here we examined the effects of Rof on behavioral dysfunction and the related mechanisms in APP/PS1 double transgenic mice,a widely used model for AD.Mice at 10 months of age were first tested in novel object recognition for memory.The recognition index in APP/PS1 mice was decreased compared to WT mice,which was reversed by Rof at 5 and 10 mg·kg-1.This was then verified in the Morris water-maze test.The 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 Rof.In the tail-suspension and forced-swimming tests,which measure depression-like behavior,APP/PS1 mice showed prolonged immobility time,which was reversed by Rof.In addition,the staining of HE and Nissl showed that Rof reduced the loss of neurons and neurocyte apoptosis in APP/PS1 mice.It 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 mice.Finally,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 mice.Overall,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 neuroprotection.Therefore,Rof can be a therapeutic agent for AD,in particular the comorbidity of memory deficits and depression.

关 键 词：Alzheimer’s disease ROFLUMILAST PDE4 cAMP signaling APP/PS1 mice COGNITION DEPRESSION 

分 类 号：R73[医药卫生—肿瘤]