PT - JOURNAL ARTICLE AU - Zheng-Qiang Zou AU - Jia-Jia Chen AU - Hong-Fang Feng AU - Yu-Fang Cheng AU - Hai-Tao Wang AU - Zhong-Zhen Zhou AU - Hai-Biao Guo AU - Wenhua Zheng AU - Jiang-Ping Xu TI - Novel Phosphodiesterase 4 Inhibitor FCPR03 Alleviates Lipopolysaccharide-Induced Neuroinflammation by Regulation of cAMP/PKA/CREB Signaling Pathway and NF-κB Inhibition AID - 10.1124/jpet.116.239608 DP - 2017 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - jpet.116.239608 4099 - http://jpet.aspetjournals.org/content/early/2017/04/27/jpet.116.239608.short 4100 - http://jpet.aspetjournals.org/content/early/2017/04/27/jpet.116.239608.full AB - Over activation of microglia contributes to the induction of neuroinflammation, 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 effect of FCPR03 both in vitro and in vivo and try to explore whether those effects were regulated by PDE4-mediated signaling pathway. BV-2 microglial cells stimulated by lipopolysaccharide (LPS) and mice intraperitoneally injected by LPS were established as in vitro and in vivo models of inflammation. Our results showed that FCPR03 dose-dependently suppressed the production of TNF-α, IL-1β and IL-6 in BV-2 microglial cells treated with LPS. Interestingly, the role of FCPR03 on the production of pro-inflammatory factors was reversed by pretreatment with Protein kinase A (PKA) inhibitor H89. In addition, FCPR03 reduced the levels of pro-inflammatory factors in the hippocampus and cortex of mice injected with LPS. Our results further demonstrated FCPR03 effectively increased production of cAMP, promoted cAMP response element binding protein (CREB) phosphorylation and inhibited nuclear factor kappa B (NF-κB) activation both in vitro and in vivo. Our findings suggest that FCPR03 inhibits the neuroinflammatory response through the activation of cAMP/PKA/CREB signaling pathways and NF-κB inhibition.