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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
- Source :
- Neuropharmacology. 116:260-269
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
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.
- Subjects :
- Male
0301 basic medicine
Genetically modified mouse
medicine.medical_specialty
Morris water navigation task
Mice, Transgenic
Stimulation
CREB
Hippocampus
Xylazine
Amyloid beta-Protein Precursor
Random Allocation
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Western blot
Alzheimer Disease
Internal medicine
Cyclic AMP
Presenilin-1
medicine
Animals
Humans
Ketamine
Cyclic AMP Response Element-Binding Protein
Furans
Nootropic Agents
Rolipram
Pharmacology
Memory Disorders
Dose-Response Relationship, Drug
Molecular Structure
medicine.diagnostic_test
biology
Learning Disabilities
business.industry
Anti-Inflammatory Agents, Non-Steroidal
Cyclic AMP-Dependent Protein Kinases
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
Endocrinology
biology.protein
Phosphodiesterase 4 Inhibitors
business
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 00283908
- Volume :
- 116
- Database :
- OpenAIRE
- Journal :
- Neuropharmacology
- Accession number :
- edsair.doi.dedup.....ef5303d45b77b70d56f4ff7b1cd24140