Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Neuropharmacology and Drug Discovery Group, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China; Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, China.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 2;90:62-75. doi: 10.1016/j.pnpbp.2018.10.017. Epub 2018 Nov 1.
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.
经典的磷酸二酯酶 4（PDE4）抑制剂在多种动物模型中产生抗抑郁样作用。然而，严重的副作用，特别是呕吐和恶心，限制了它们的临床应用。FCPR16 是一种新型 PDE4 抑制剂，其致吐潜力较低。然而，它是否会产生抗抑郁样作用尚不清楚。在这里，我们旨在评估 FCPR16 在慢性不可预测轻度应激（CUMS）小鼠中的作用。我们的结果表明，FCPR16 在多种行为测试中产生抗抑郁样作用，包括强迫游泳试验、悬尾试验、蔗糖偏好试验和新奇抑制喂养试验。同时，数据表明，FCPR16 增强了 cAMP、脑源性神经营养因子、cAMP 直接激活交换蛋白 2（EPAC-2）、突触素 1、突触后密度蛋白 95、磷酸化 cAMP 反应元件结合蛋白和细胞外调节蛋白激酶 1/2 的水平，这些水平在 CUMS 后皮质和海马中均降低。FCPR16 治疗后，CUMS 小鼠海马中的 DCX 细胞数量增加。此外，FCPR16 治疗导致 CUMS 小鼠促炎细胞因子（TNF-α、IL-6 和 IL-1β）表达减少，抗炎细胞因子（IL-10）表达增加。同样，FCPR16 处理后，CUMS 暴露小鼠小胶质细胞 M1 标志物（iNOS 和 TNF-α）的 mRNA 水平下调，而 M2 标志物（精氨酸酶 1 和 CD206）上调。免疫荧光分析表明，FCPR16 抑制了小胶质细胞的激活，并增加了 CUMS 暴露小鼠中 CD206 的数量。总之，这些结果表明，FCPR16 是一种具有抗抑郁样行为作用的潜在化合物，FCPR16 的抗抑郁样作用可能是通过激活 cAMP 介导的信号通路和抑制皮质和海马中的神经炎症来介导的。
