School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Clinical Trial Center, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
Brain Behav Immun. 2021 Feb;92:67-77. doi: 10.1016/j.bbi.2020.11.029. Epub 2020 Nov 20.
Inhibition of phosphodiesterase-4 (PDE4) produces robust anti-inflammatory and antidepressant-like effects in multiple animal models. However, the detailed mechanisms have not been well studied. Receptor for advanced glycation endproducts (RAGE) and inflammasome activation are implicated in the etiology of depression. Here, we aimed to investigate the involvement of RAGE and nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in the antidepressant-like effects of PDE4 inhibition in mice. We found that inhibition of PDE4 by roflupram (ROF, 0.5, and 1.0 mg/kg, i.g.) exerted antidepressant-like effects in mice subjected to chronic unpredictable mild stress (CUMS). Simultaneously, ROF inhibited CUMS-induced microglial activation and restored the morphology of microglial cells in the hippocampus, as evidenced by reduced total process length, area, volume, number of branching points, number of terminal points and total sholl intersections of microglia. ROF also decreased the expression of ionized calcium-binding adapter molecule-1 and the level of interleukin-1β. Western blot analysis showed that PDE4 inhibition suppressed the high-mobility group box 1 protein (HMGB1)/RAGE signaling pathway, as the levels of HMGB1, RAGE, toll-like receptor 4, phosphorylated p38 mitogen-activated protein kinase, and nuclear factor κ-B were decreased in both hippocampus and cortex in mice after treatment with ROF. Moreover, ROF also attenuated the protein levels of NLRP3, the apoptosis-associated speck-like protein containing (ASC), and cysteine-requiring aspartate protease-1 (Caspase-1), which are key proteins in the NLRP3-mediated inflammasome signaling pathway. In summary, these results demonstrate that the down-regulation of HMGB1/RAGE signaling pathway and inflammasome suppression possibly contribute to the antidepressant-like effects of PDE4 inhibitors. And, ROF has potential as a candidate drug in the treatment of depression.
磷酸二酯酶 4（PDE4）抑制剂在多种动物模型中产生强大的抗炎和抗抑郁样作用。然而，其详细机制尚未得到很好的研究。晚期糖基化终产物受体（RAGE）和炎症小体激活与抑郁症的发病机制有关。在这里，我们旨在研究 RAGE 和核苷酸结合域（NOD）样受体蛋白 3（NLRP3）炎症小体在 PDE4 抑制剂对小鼠的抗抑郁作用中的作用。我们发现，罗氟司特（ROF，0.5 和 1.0mg/kg，ig）抑制 PDE4 在慢性不可预测轻度应激（CUMS）小鼠中表现出抗抑郁样作用。同时，ROF 抑制 CUMS 诱导的小胶质细胞活化并恢复海马中小胶质细胞的形态，表现为小胶质细胞总突起长度、面积、体积、分支点数量、末端点数量和总 Sholl 交点减少。ROF 还降低了离子钙结合接头分子-1 和白细胞介素-1β的水平。Western blot 分析表明，PDE4 抑制抑制高迁移率族蛋白 B1（HMGB1）/RAGE 信号通路，因为 ROF 处理后小鼠海马和皮质中 HMGB1、RAGE、Toll 样受体 4、磷酸化 p38 丝裂原激活蛋白激酶和核因子 κ-B 的水平降低。此外，ROF 还减弱了 NLRP3 介导的炎症小体信号通路中的关键蛋白 NLRP3、凋亡相关斑点样蛋白（ASC）和半胱氨酸天冬氨酸蛋白酶-1（Caspase-1）的蛋白水平。总之，这些结果表明，HMGB1/RAGE 信号通路的下调和炎症小体的抑制可能是 PDE4 抑制剂抗抑郁样作用的原因。并且，ROF 有可能成为治疗抑郁症的候选药物。
