title: FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signaling and anti-inflammatory effects.
abstract: Thus far, phosphodiesterase-4 (PDE4) inhibitors have not been approved for application in Alzheimer's disease (AD) in a clinical setting due to severe side effects, such as nausea and vomiting. In this study, we investigated the effect of FFPM, a novel PDE4 inhibitor, on learning and memory abilities, as well as the underlying mechanism in the APP/PS1 mouse model of AD. Pharmacokinetic studies have revealed that FFPM efficiently permeates into the brain, and reached peak values in plasma 2 h after orally dosing. A 3-week treatment with FFPM, at doses of 0.25 mg/kg and 0.5 mg/kg, significantly improved the learning and memory abilities of APP/PS1 transgenic mice in the Morris water maze and the Step-down passive avoidance task. Interestingly, we found that while rolipram (0.5 mg/kg) reduced the duration of the α2 adrenergic receptor-mediated anesthesia induced by xylazine/ketamine, FFPM (0.5 mg/kg) or the vehicle did not have an evident effect. FFPM increased the cAMP, PKA and CREB phosphorylation and BDNF levels, and reduced the NF-κB p65, iNOS, TNF-α and IL-1β levels in the hippocampi of APP/PS1 trangenic mice, as observed by ELISA and Western blot analysis. Taken together, our data demonstrated that the reversal effect of FFPM on cognitive deficits in APP/PS1 transgenic mice might be related to stimulation of the cAMP/PKA/CREB/BDNF pathway and anti-inflammatory effects. Moreover, FFPM appears to have potential as an effective PDE4 inhibitor in AD treatment with little emetic potential.
authors.affiliation: Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Modern Chinese Medicine Research Institute of Hutchison Whampoa Guangzhou Baiyunshan Chinese Medicine Co., Ltd., Guangzhou 510515, China.
authors.forename: Haibiao
authors.initials: H
authors.lastname: Guo
authors.affiliation: Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Pharmacy, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, 518000, China.
authors.forename: Canmao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jingang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Zhengqiang
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Niu
authors.affiliation: Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.affiliation: Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: wht821@smu.edu.cn.
authors.forename: Haitao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: jpx@smu.edu.cn.
authors.forename: Jiangping
authors.initials: J
authors.lastname: Xu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000276:immunology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007859:Learning Disabilities / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015394:Molecular Structure; D018697:Nootropic Agents / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D058988:Phosphodiesterase 4 Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation
chemical_list: C000626968:1-(4-(difluoromethoxy)-3-((tetrahydrofuran-3-yl)oxy)phenyl)-3-methylbutan-1-one; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D005663:Furans; D018697:Nootropic Agents; C508853:PSEN1 protein, human; D058988:Phosphodiesterase 4 Inhibitors; D053764:Presenilin-1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Alzheimer's disease; Anti-inflammation; Cognition; FFPM; Phosphodiesterase-4; cAMP-response element binding protein