Novel Phosphodiesterase 4 Inhibitor FCPR03 Alleviates Lipopolysaccharide-Induced Neuroinflammation by Regulation of the cAMP/PKA/CREB Signaling Pathway and NF-κB Inhibition

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 , interleukin-1, 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 B (NF-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-B inhibition.

Leucine-rich repeat kinase 2 controls protein kinase A activation state through phosphodiesterase 4

“…In particular, PDEs play a crucial role in controlling the magnitude and the duration of PKA signaling [ 37 ]. Given this key function of PDEs and the established link between PDE4 and inflammatory responses in microglia [ 38 – 41 ], we investigated whether LRRK2 activity affects cAMP levels in microglia. We found that cells treated with LRRK2 kinase inhibitor exhibit increased levels of cAMP compared to control cells, indicating that LRRK2 activity affects cAMP degradation.…”

Targeting phosphodiesterase 4 as a potential therapeutic strategy for enhancing neuroplasticity following ischemic stroke

“…Inhibition of PDE4 is effective to suppress the production of IL-1. Our previous studies have shown that inhibition or silencing of PDE4 attenuated the level of IL-1β in β amyloid-injected mice 50 , APP/PS1 transgenic mice 119 and lipopolysaccharide-treated mice 14 , 130 . Consistently, another independent study showed that the SNPs in the PDE4D (83T/C) and IL-1 (-889C/T) were related with high risk of the occurrence of ischemic stroke 131 .…”

“…Among various PDE family proteins, phosphodiesterase 4 (PDE4) specifically hydrolyzes cAMP and inhibition of PDE4 is an ideal strategy for the prevention and treatment of peripheral inflammation and immune diseases, such as pulmonary inflammation and psoriasis 13 . In the CNS, PDE4 plays a key role in both chronic neurodegenerative diseases and acute neurological insults, including stroke 14 , 15 . Recently, an increasing number of reports have shown that inhibition of PDE4 is beneficial for neuroplasticity 16 - 18 , making it a promising candidate target that has therapeutic potential for the recovery of stroke.…”

Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases

“…In vitro , FCPR03 inhibited the immune responses in LPS-stimulated BV-2 cells, a microglial cell line, and its anti-inflammatory effects could be blocked by a PKA inhibitor, H89. In vivo , FCPR03 suppressed pro-inflammatory mediators by increasing the level of cAMP, promoting CREB phosphorylation, and inhibiting NF-κB activation in the cortex and hippocampus of LPS-immunized mice (Zou et al, 2017 ). Furthermore, a study in mice challenged by LPS found that 1 mg/kg/day FCPR03 showed anti-depressant effects as confirmed by the decrease in depressant-like behaviors with the duration of immobility in the forced swim and tail suspension tests (Yu et al, 2018 ).…”