Inhibition of Phosphodiesterase 4 by FCPR03 Alleviates Chronic Unpredictable Mild Stress-induced Depressive-like Behaviors and Prevents Dendritic Spine Loss in Mice Hippocampi.
Mots clés
Abstrait
UNASSIGNED
Phosphodiesterase 4 (PDE4) is a promising target for developing novel antidepressants. However, prototype PDE4 inhibitors show severe side effects, including nausea and vomiting. FCPR03 is a novel PDE4 inhibitor with little emetic potential. In the present study, we investigated the inhibitory effect of FCPR03 on chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors in mice and explored the underlying mechanisms.
UNASSIGNED
The depression model of mice was established by CUMS. Forced swim test (FST), tail suspension test (TST) and sucrose preference test (SPT) 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 ELISA assay. Western blot was used to evaluate protein levels of phosphorylated cAMP-response element binding protein (CREB), protein kinase B (Akt), glycogen synthase kinase-3β (GSK-3β), brain derived neurotrophic factor (BDNF) in both hippocampus and prefrontal cortex. Postsynaptic density protein 95 (PSD95) and synapsin 1 were also detected by Western blot in the hippocampi.
UNASSIGNED
Treatment with FCPR03 (0.5-1.0 mg/kg, i.p.) increased consumption of sucrose in SPT in mice exposed to CUMS. FCPR03 shorten the immobility time in FST and TST without affecting the locomotor activity. Furthermore, CUMS decreased the dendritic spine density and dendritic length in the hippocampus. This change was accompanied by decreased expression of PSD95 and synapsin 1. Interestingly, FCPR03 prevented dendritic spine loss and increased synaptic protein levels. Moreover, the levels of cAMP, phosphorylated CREB and BDNF were elevated in CUMS-challenged mice after treatment with FCPR03. In addition, FCPR03 also enhanced the phosphorylation of both Akt and GSK-3β in mice exposed to CUMS.
UNASSIGNED
The present study suggests that FCPR03 could prevent both depressive-like behaviors and spine loss induced by CUMS in the mice hippocampi.
