Abstract
Overactivation 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 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 α, interleukin-1β, 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 κB (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 pathway and NF-κB inhibition.
Footnotes
- Received December 17, 2016.
- Accepted April 20, 2017.
This work was supported by the National Science and Technology Major Projects of China for Major New Drug Innovation and Development (Grant 2012ZX09J1211003C) and the National Natural Science Foundation of China (Grant 81373384 and 81503043) Science and Technology Planning Project of Guangdong Province (Grant 2012B050500005 and 2015B020211007).
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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