Roflumilast ameliorates cognitive impairment in APP/PS1 mice via cAMP/CREB/BDNF signaling and anti-neuroinflammatory effects

  • Huancun Feng
  • Canmao Wang
  • Wei He
  • Xinjun Wu
  • Shujie Li
  • Zhenkun Zeng
  • Meidan Wei
  • Binghong HeEmail author
Original Article


Phosphodiesterase type 4 (PDE4) inhibitors can prevent the breakdown of the second messenger cyclic adenosine monophosphate (cAMP) and improve cognitive performances in several animal models of cognition. However, the clinical development of PDE4 inhibitors has been seriously hampered by severe side effects, such as vomiting and nausea. In this study, we investigated the effect and mechanism of roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), on learning and memory abilities in the APP/PS1 mouse model of Alzheimer’s disease (AD). APP/PS1 transgenic mice received 3 intragastric doses of roflumilast (0.1, 0.2 and 0.4 mg/kg) daily for 3 weeks followed by behavioral tests. Chronic administration of roflumilast significantly improved the learning and memory abilities of APP/PS1 transgenic mice in the novel object recognition task, Morris water maze, and the step-down passive avoidance task. In addition, roflumilast increased the cAMP, phosphorylated cAMP response-element binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) levels, and reduced the nuclear translocation of nuclear factor-kappa B (NF-κB) p65, and proinflammatory cytokine (IL-6, TNF-a and IL-1β) levels in the hippocampus of APP/PS1 transgenic mice. In conclusion, these findings suggest that roflumilast can enhance cognitive function in APP/PS1 transgenic mice, which may be related to its stimulation of the cAMP/CREB/BDNF pathway and anti-neuroinflammatory effects.


Roflumilast Phosphodiesterase-4 Alzheimer’s disease cAMP-response element binding protein (CREB) Neuroinflammation Cognition 



This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflicts of interest

The authors declare that there are no conflicts of interest.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacy, The Third Affiliated HospitalSouthern Medical UniversityGuangzhouChina
  2. 2.Department of PharmacyShenzhen University General HospitalShenzhenChina
  3. 3.Department of BiologyEast Carolina UniversityGreenvilleUSA

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