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FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signaling and anti-inflammatory effects.
Neuropharmacology. 2017 04; 116:260-269.N

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.

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Authors+Show Affiliations

Guo H
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.
Cheng Y
Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Wang C
Department of Pharmacy, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, 518000, China.
Wu J
Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Zou Z
Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Niu B
Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Yu H
Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Wang H
Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: wht821@smu.edu.cn.
Xu J
Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: jpx@smu.edu.cn.

MeSH

Alzheimer DiseaseAmyloid beta-Protein PrecursorAnimalsAnti-Inflammatory Agents, Non-SteroidalCyclic AMPCyclic AMP Response Element-Binding ProteinCyclic AMP-Dependent Protein KinasesDisease Models, AnimalDose-Response Relationship, DrugFuransHippocampusHumansLearning DisabilitiesMaleMemory DisordersMice, Inbred C57BLMice, TransgenicMolecular StructureNootropic AgentsPhosphodiesterase 4 InhibitorsPresenilin-1Random Allocation

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28065587

Citation

Guo, Haibiao, et al. "FFPM, a PDE4 Inhibitor, Reverses Learning and Memory Deficits in APP/PS1 Transgenic Mice Via cAMP/PKA/CREB Signaling and Anti-inflammatory Effects." Neuropharmacology, vol. 116, 2017, pp. 260-269.
Guo H, Cheng Y, Wang C, et al. FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signaling and anti-inflammatory effects. Neuropharmacology. 2017;116:260-269.
Guo, H., Cheng, Y., Wang, C., Wu, J., Zou, Z., Niu, B., Yu, H., Wang, H., & Xu, J. (2017). FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signaling and anti-inflammatory effects. Neuropharmacology, 116, 260-269. https://doi.org/10.1016/j.neuropharm.2017.01.004
Guo H, et al. FFPM, a PDE4 Inhibitor, Reverses Learning and Memory Deficits in APP/PS1 Transgenic Mice Via cAMP/PKA/CREB Signaling and Anti-inflammatory Effects. Neuropharmacology. 2017;116:260-269. PubMed PMID: 28065587.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signaling and anti-inflammatory effects. AU - Guo,Haibiao, AU - Cheng,Yufang, AU - Wang,Canmao, AU - Wu,Jingang, AU - Zou,Zhengqiang, AU - Niu,Bo, AU - Yu,Hui, AU - Wang,Haitao, AU - Xu,Jiangping, Y1 - 2017/01/06/ PY - 2016/07/21/received PY - 2016/12/25/revised PY - 2017/01/05/accepted PY - 2017/1/10/pubmed PY - 2018/5/10/medline PY - 2017/1/10/entrez KW - Alzheimer's disease KW - Anti-inflammation KW - Cognition KW - FFPM KW - Phosphodiesterase-4 KW - cAMP-response element binding protein SP - 260 EP - 269 JF - Neuropharmacology JO - Neuropharmacology VL - 116 N2 - 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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/28065587/FFPM_a_PDE4_inhibitor_reverses_learning_and_memory_deficits_in_APP/PS1_transgenic_mice_via_cAMP/PKA/CREB_signaling_and_anti_inflammatory_effects_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(17)30004-7 DB - PRIME DP - Unbound Medicine ER -