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Novel Phosphodiesterase 4 Inhibitor FCPR03 Alleviates Lipopolysaccharide-Induced Neuroinflammation by Regulation of the cAMP/PKA/CREB Signaling Pathway and NF-kappa B Inhibition
Zou, Zheng-Qiang; Chen, Jia-Jia; Feng, Hong-Fang; Cheng, Yu-Fang; Wang, Hai-Tao; Zhou, Zhong-Zhen; Guo, Hai-Biao; Zheng, Wenhua; Xu, Jiang-Ping
2017-07
Source PublicationJOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN0022-3565
Volume362Issue:1Pages:67-77
AbstractOveractivation of microglia contributes to the induction of neuro-inflammation, which is highly involved in the pathology of many neurodegenerative diseases. Phosphodiesterase 4 (PDE4) represents a promising therapeutic target for anti-inflammation; however, the dose-limiting side effects, such as nausea and emesis, have impeded their clinic application. FCPR03, a novel selective PDE4 inhibitor synthesized in our laboratory, shows little or no emetic potency; however, the anti-inflammatory activities of FCPR03 in vitro and in vivo and the molecular mechanisms are still not clearly understood. This study was undertaken to delineate the anti-inflammatory effects of FCPR03 both in vitro and in vivo and explore whether these effects are regulated by PDE4-mediated signaling pathway. BV-2 microglial cells stimulated by lipopolysaccharide (LPS) and mice injected i.p. with LPS were established as in vitro and in vivo models of inflammation. Our results showed that FCPR03 dose dependently suppressed the production of tumor necrosis factor alpha, interleukin-1 beta, and iinterleukin-6 in BV-2 microglial cells treated with LPS. The role of FCPR03 in the production of proinflammatory factors was reversed by pretreatment with protein kinase A (PKA) inhibitor H89. In addition, FCPR03 reduced the levels of proinflammatory factors in the hippocampus and cortex of mice injected with LPS. Our results further demonstrated that FCPR03 effectively increased the production of cAMP, promoted cAMP response element binding protein (CREB) phosphorylation, and inhibited nuclear factor kappa B (NF-kappa B) activation both in vitro and in vivo. Our findings suggest that FCPR03 inhibits the neuroinflammatory response through the activation of cAMP/PKA/CREB signaling pathway and NF-kappa B inhibition.
DOI10.1124/jpet.116.239608
URLView the original
Indexed BySCI
Language英语
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000402869600009
PublisherAMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
The Source to ArticleWOS
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Cited Times [WOS]:10   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Recommended Citation
GB/T 7714
Zou, Zheng-Qiang,Chen, Jia-Jia,Feng, Hong-Fang,et al. Novel Phosphodiesterase 4 Inhibitor FCPR03 Alleviates Lipopolysaccharide-Induced Neuroinflammation by Regulation of the cAMP/PKA/CREB Signaling Pathway and NF-kappa B Inhibition[J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,2017,362(1):67-77.
APA Zou, Zheng-Qiang.,Chen, Jia-Jia.,Feng, Hong-Fang.,Cheng, Yu-Fang.,Wang, Hai-Tao.,...&Xu, Jiang-Ping.(2017).Novel Phosphodiesterase 4 Inhibitor FCPR03 Alleviates Lipopolysaccharide-Induced Neuroinflammation by Regulation of the cAMP/PKA/CREB Signaling Pathway and NF-kappa B Inhibition.JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,362(1),67-77.
MLA Zou, Zheng-Qiang,et al."Novel Phosphodiesterase 4 Inhibitor FCPR03 Alleviates Lipopolysaccharide-Induced Neuroinflammation by Regulation of the cAMP/PKA/CREB Signaling Pathway and NF-kappa B Inhibition".JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 362.1(2017):67-77.
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