FCPR16, a novel phosphodiesterase 4 inhibitor, produces an antidepressant-like effect in mice exposed to chronic unpredictable mild stress

The canonical phosphodiesterase 4 (PDE4) inhibitors produce antidepressant-like effects in a variety of animal models. However, severe side effects, particularly vomiting and nausea, limit their clinical application. FCPR16 is a novel PDE4 inhibitor with less vomiting potential. However, whether it will exert an antidepressant-like effect remains unclear. Here, we aimed to evaluate the effect of FCPR16 in mice subjected to chronic unpredictable mild stress (CUMS). Our results showed that FCPR16 produced antidepressant-like effects in multiple behavioral tests, including a forced swimming test, tail suspension test , sucrose preference test and novelty suppression feeding test. Simultaneously, data indicated that FCPR16 enhanced the levels of several proteins, including cAMP, brain derived neurotrophic factor , exchange protein directly activated by cAMP 2 (EPAC-2), synapsin1, postsynaptic density protein 95 , phosphorylated cAMP response element binding protein and extracellular regulated protein kinases 1/2, which were downregulated by CUMS in both the cerebral cortex and hippocampus . The number of DCX + cells in the hippocampus of CUMS mice was increased after FCPR16 treatment. Moreover, treatment with FCPR16 resulted in decreased expression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and increased expression of anti-inflammatory cytokines (IL-10) in mice challenged with CUMS. Consistently, the mRNA levels of microglial M1 markers (iNOS and TNF-α) were downregulated, while M2 markers (Arginase 1 and CD206) were upregulated in CUMS-exposed mice after FCPR16 treatment. Immunofluorescence analysis showed that FCPR16 inhibited the activation of microglial cells and increased the number of CD206 + in CUMS-exposed mice. Collectively, these results suggested that FCPR16 is a potential compound with effects against depressive-like behaviors , and the antidepressant-like effect of FCPR16 is possibly mediated through activation of the cAMP-mediated signaling pathways and inhibition of neuroinflammation in both the cerebral cortex and hippocampus.