Effect Of PDE4 Inhibitor FCPR03 On Relieving LPS-induced Depressive-like Behaviors In Mice And Its Underlying Mechanism

Objective:Depression is a common and debilitating neuropsychiatric disorder having a complex and multifactor etiology which has lifetime prevalence,the main clinical features of this disorder is long-lasting sadness.Depression is considered to be one of major global mental health problems.In recent years,with the accelerating pace of modern life and social pressure gradually increased,the incidence of depression is increasing year by year.Accumulating evidence reveals neuroinflammation is closely associated with the pathogenesis of depression.Furthermore,more and more evidence also shows that inflammation plays an important role in the occurrence and development of depression.There is a close relationship between depression and neuroinflammation.A large number of in vitro and in vivo studies have shown that PDE4 inhibitors have significant anti-inflammatory effect,meanwhile,they also exert antidepressant effect through up-regulating cAMP/PKA/CREB signaling pathway.However,severe nausea and vomiting adverse reactions limit their clinical application.FCPR03 is a novel PDE4 inhibitor designed and synthesized in our lab.Our preliminary results show that FCPR03 has a high selectivity to PDE4 enzyme.Based on the neuroinflammation hypothesis of depression,we used LPS to establish the model of depression induced by inflammation to evaluate the effect of FCPR03 on the depression-like behavior of LPS-induced mice.Furthermore,to study the anti-neuroinflammatory effect of FCPR03 and its mechanism,LPS was used to induce BV-2 microglia activation as a neuroinflammatory model in vitro.Our study provides a theoretical basis for finding new drugs that can improve the depression-like behavior mediated by inflammation.Methods:(1)Behavioral Despair Model was used to estimate the antidepressant effect of FCPR03 through calculating the immobility time in Tail Suspension and Forced Swimming Test.(2)The depression mouse model induced by inflammation was established by intraperitoneal injection of 1.2 mg/kg LPS.Then,the effect of FCPR03 on relieving LPS-induced depressive-like behaviors in mice and its underlying mechanism were investigated.(3)Induction of BV-2 microglia activation by 1 μg/ml LPS was used to simulate the neuroinflammation model in vitro and to evaluate the anti-neuroinflammatory effect of FCPR03.(4)The vomiting potential of FCPR03 was evaluated by observing the recovery time of righting reflex in mice induced by ketamine/xylazine and the vomiting test of beagle dogs.Results:(1)There were no statistical differences in the scores of the ambulation and rearing in the open field test between the mice injected intraperitoneally with different doses of FCPR03 for 30 min.In the tail suspension and forced swimming experiments,the immobility time was significantly decreased following the administration of FCPR03,indicating hat CPR03 has a potential antidepressant effect.(2)After mice were injected with 1.2 mg/kg LPS for 24 h,the body weight of mice were decreased significantly,while the immobility time of the mice were significantly increased in the tail suspension and forced swimming test,and after 7 days of continuous administration of FCPR03,the immobility time were dramatically reduced and the sucrose preference index were increased,suggesting that FCPR03 can improve LPS-induced depression-like behavior of mice.(3)Furthermore,FCPR03 could up-regulate cAMP/PKA/CREB signaling pathway,inhibit the phosphorylation of p38 and JNK and the activation of NF-κB,finally,the release of inflammatory cytokines and neuroinflammation were inhibited,leading to an improvement of LPS-induced depressed-like behavior in mice.(4)Compared with normal group,FCPR03 had no statistical difference in the recovery time of righting reflex in the combined anesthesia of xylazine and ketamine,and did not induce the vomiting reaction of beagle dogs,suggesting that FCPR03 has lower vomiting potential.Conclusion:In this study,our results showed that FCPR03 could improve LPS-induced depressive behavior mainly through up-regulating cAMP/PKA/CREB signaling pathway.Our results also revealed that FCPR03 could decrease the phosphorylation levels of p38 and JNK,inhibit the activation of NF-κB,inhibit the release of inflammatory cytokines and decrease the neuroinflammation of central nervous system.At the same time,FCPR03 has low vomiting potential,suggesting that FCPR03 is a potential antidepressant drug candidate.