Inhibition of Phosphodiesterase 4 by FCPR03 Alleviates Chronic Unpredictable Mild Stress-Induced Depressive-Like Behaviors and Prevents Dendritic Spine Loss in Mice Hippocampi.

Background: Phosphodiesterase 4 is a promising target for developing novel antidepressants. However, prototype phosphodiesterase 4 inhibitors show severe side effects, including nausea and vomiting. N-Isopropyl-3-(cyclopropylmethoxy)-4-difluoromethoxy benzamide (FCPR03) is a novel phosphodiesterase 4 inhibitor with little emetic potential. In the present study, we investigated the inhibitory effect of FCPR03 on chronic unpredictable mild stress-induced, depressive-like behaviors in mice and explored the underlying mechanisms. Methods: The depression model of mice was established by chronic unpredictable mild stress. Forced swim test, tail suspension test, and sucrose preference test were used to assess depressive-like behaviors. Golgi-staining was utilized to analyze dendritic morphology and spine density. The level of cAMP was measured by enzyme-linked immnosorbent assay assay. Western blot was used to evaluate protein levels of phosphorylated cAMP-response element binding protein, protein kinase B, glycogen synthase kinase-3β, and brain derived neurotrophic factor in both hippocampus and prefrontal cortex. Postsynaptic density protein 95 and synapsin 1 were also detected by western blot in the hippocampi. Results: Treatment with FCPR03 (0.5-1.0 mg/kg, i.p.) increased consumption of sucrose in the sucrose preference test in mice exposed to chronic unpredictable mild stress. FCPR03 shortened the immobility time in forced swim test and tail suspension test without affecting locomotor activity. Furthermore, chronic unpredictable mild stress decreased the dendritic spine density and dendritic length in the hippocampus. This change was accompanied by decreased expression of postsynaptic density protein 95 and synapsin 1. Interestingly, FCPR03 prevented dendritic spine loss and increased synaptic protein levels. Moreover, the levels of cAMP, phosphorylated cAMP-response element binding protein, and brain derived neurotrophic factor were elevated in chronic unpredictable mild stress-challenged mice after treatment with FCPR03. In addition, FCPR03 also enhanced the phosphorylation of both protein kinase B and glycogen synthase kinase-3β in mice exposed to chronic unpredictable mild stress. Conclusion: The present study suggests that FCPR03 could prevent both depressive-like behaviors and spine loss induced by chronic unpredictable mild stress in the mice hippocampi.