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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.

Authors+Show Affiliations

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.Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.Department of Pharmacy, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, 518000, China.Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: wht821@smu.edu.cn.Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: jpx@smu.edu.cn.

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 -