Inhibition of Phosphodiesterase 4 by FCPR03 Alleviates Lipopolysaccharide-Induced Depressive-Like Behaviors in Mice: Involvement of p38 and JNK Signaling Pathways.

Hui Yu,Yicheng Ye,Wanli Peng,Jiangping Xu,Xiaolin Zhang,Zhengqiang Zou,Haitao Wang,Chen Chen

doi:10.3390/ijms19020513

Abstract

Inflammatory responses induced by peripheral administration of lipopolysaccharide (LPS) triggers depressive-like behavioral syndrome in rodents. Inhibition of phosphodiesterase 4 (PDE4) produces a robust anti-inflammatory effect in inflammatory cells. Unfortunately, archetypal PDE4 inhibitors cause intolerable gastrointestinal side-effects, such as vomiting and nausea. N-isopropyl-3-(cyclopropylmethoxy)-4-difluoromethoxy benzamide (FCPR03) is a novel, selective PDE4 inhibitor with little, or no, emetic potency. Our previous studies show that FCPR03 is effective in attenuating neuroinflammation in mice treated with LPS. However, whether FCPR03 could exert antidepressant-like effect induced by LPS is largely unknown. In the present study, mice injected intraperitoneally (i.p.) with LPS was established as an in vivo animal model of depression. The antidepressant-like activities of FCPR03 were evaluated using a tail suspension test, forced swimming test, and sucrose preference test. We demonstrated that administration of FCPR03 (1 mg/kg) produced antidepressant-like effects in mice challenged by LPS, as evidenced by decreases in the duration of immobility in the forced swim and tail suspension tests, while no significant changes in locomotor activity were observed. FCPR03 also increased sucrose preference in mice treated with LPS. In addition, treatment with FCPR03 abolished the downregulation of brain-derived neurotrophic factor induced by LPS and decreased the level of corticosterone in plasma. Meanwhile, periphery immune challenge by LPS induced enhanced phosphorylation of p38-mitogen activated protein kinase (p38) and c-Jun N-terminal kinase (JNK) in both the cerebral cortex and hippocampus in mice. Interestingly, treatment with FCPR03 significantly blocked the role of LPS and reduced the levels of phosphorylated p38 and JNK. Collectively, these results indicate that FCPR03 shows antidepressant-like effects in mice challenged by LPS, and the p38/JNK signaling pathway is possibly involved in this process. Our findings suggest that FCPR03 is a potential compound for the prevention or treatment of depression.

Highlights

Depression is a common and debilitating neuropsychiatric disorder with increasing incidence year by year
Activated protein kinase A (PKA) inhibits the production of nitric oxide and reduces the expression of inducible nitric oxide synthase and tumor necrosis factor-α (TNF-α), These effects are associated with a decrease in nuclear factor-κB (NF-κB) p65 DNA binding [22]
Our previous studies found that FCPR03 inhibited LPS-induced expression of TNF-α, IL-1β, and inducible nitric oxide synthase (iNOS) through activating the cyclic adenosine monophosphate (cAMP)/PKA/cAMP-response element binding protein (CREB) signaling pathway and inhibition of NF-κB in microglial cells [32,33]

Summary

Introduction

Depression is a common and debilitating neuropsychiatric disorder with increasing incidence year by year. Deficiency of monoamine transmitters in the synaptic cleft is the most acceptable explanation for this disorder [3], and most of the commercially-available drugs are developed based on this theory [3] Current antidepressants, such as serotonin reuptake inhibitors, are effective in alleviating the clinical symptoms of depression through enhancing the level of neurotransmitters in the synaptic cleft. Activated PKA inhibits the production of nitric oxide and reduces the expression of inducible nitric oxide synthase (iNOS) and TNF-α, These effects are associated with a decrease in nuclear factor-κB (NF-κB) p65 DNA binding [22]. Our previous studies found that FCPR03 inhibited LPS-induced expression of TNF-α, IL-1β, and iNOS through activating the cAMP/PKA/CREB signaling pathway and inhibition of NF-κB in microglial cells [32,33]. Whether JNK and p38 signaling pathways are involved in the anti-depressant-like effects of this compound were assessed

Results

FCPR03 Decreased the Level of Plasma Corticosterone in LPS-Treated Mice

FCPR03 Increased the Phosphorylation of p38 and JNK in LPS-Treated Mice

Animals

Drug Preparation and Treatment

Mouse Model of Depression

Sucrose Preference Test

Open Field Test

Forced Swim Test and Tail Suspension Test

Western Blot Analysis

Statistical Analysis