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Roflumilast ameliorates cognitive impairment in APP/PS1 mice via cAMP/CREB/BDNF signaling and anti-neuroinflammatory effects.
Metab Brain Dis. 2019 04; 34(2):583-591.MB

Abstract

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.

Authors+Show Affiliations

Department of Pharmacy, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510000, Guangdong, China.Department of Pharmacy, Shenzhen University General Hospital, Shenzhen, 518000, Guangdong, China.Department of Pharmacy, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510000, Guangdong, China.Department of Biology, East Carolina University, Greenville, NC, 27858, USA.Department of Pharmacy, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510000, Guangdong, China.Department of Pharmacy, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510000, Guangdong, China.Department of Pharmacy, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510000, Guangdong, China.Department of Pharmacy, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510000, Guangdong, China. he200666@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30610438

Citation

Feng, Huancun, et al. "Roflumilast Ameliorates Cognitive Impairment in APP/PS1 Mice Via cAMP/CREB/BDNF Signaling and Anti-neuroinflammatory Effects." Metabolic Brain Disease, vol. 34, no. 2, 2019, pp. 583-591.
Feng H, Wang C, He W, et al. Roflumilast ameliorates cognitive impairment in APP/PS1 mice via cAMP/CREB/BDNF signaling and anti-neuroinflammatory effects. Metab Brain Dis. 2019;34(2):583-591.
Feng, H., Wang, C., He, W., Wu, X., Li, S., Zeng, Z., Wei, M., & He, B. (2019). Roflumilast ameliorates cognitive impairment in APP/PS1 mice via cAMP/CREB/BDNF signaling and anti-neuroinflammatory effects. Metabolic Brain Disease, 34(2), 583-591. https://doi.org/10.1007/s11011-018-0374-4
Feng H, et al. Roflumilast Ameliorates Cognitive Impairment in APP/PS1 Mice Via cAMP/CREB/BDNF Signaling and Anti-neuroinflammatory Effects. Metab Brain Dis. 2019;34(2):583-591. PubMed PMID: 30610438.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Roflumilast ameliorates cognitive impairment in APP/PS1 mice via cAMP/CREB/BDNF signaling and anti-neuroinflammatory effects. AU - Feng,Huancun, AU - Wang,Canmao, AU - He,Wei, AU - Wu,Xinjun, AU - Li,Shujie, AU - Zeng,Zhenkun, AU - Wei,Meidan, AU - He,Binghong, Y1 - 2019/01/04/ PY - 2018/06/11/received PY - 2018/12/19/accepted PY - 2019/1/6/pubmed PY - 2019/8/14/medline PY - 2019/1/6/entrez KW - Alzheimer’s disease KW - Cognition KW - Neuroinflammation KW - Phosphodiesterase-4 KW - Roflumilast KW - cAMP-response element binding protein (CREB) SP - 583 EP - 591 JF - Metabolic brain disease JO - Metab Brain Dis VL - 34 IS - 2 N2 - 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. SN - 1573-7365 UR - https://www.unboundmedicine.com/medline/citation/30610438/Roflumilast_ameliorates_cognitive_impairment_in_APP/PS1_mice_via_cAMP/CREB/BDNF_signaling_and_anti_neuroinflammatory_effects_ L2 - https://doi.org/10.1007/s11011-018-0374-4 DB - PRIME DP - Unbound Medicine ER -