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 NLRP-3-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.

中文翻译：

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抑制磷酸二酯酶 4 可抑制暴露于慢性不可预测轻度应激的小鼠的 HMGB1/RAGE 信号通路和 NLRP3 炎性体激活

抑制磷酸二酯酶 4 (PDE4) 在多种动物模型中产生强大的抗炎和抗抑郁样作用。然而，详细的机制尚未得到很好的研究。晚期糖基化终产物 (RAGE) 受体和炎症小体激活与抑郁症的病因有关。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 抑制对小鼠的抗抑郁样作用中的作用。我们发现罗氟普兰 (ROF, 0.5 和 1.0 mg/kg, ig) 对 PDE4 的抑制在遭受慢性不可预知的轻度应激 (CUMS) 的小鼠中发挥抗抑郁样作用。同时，ROF抑制了CUMS诱导的小胶质细胞活化，恢复了海马小胶质细胞的形态，正如小胶质细胞的总过程长度、面积、体积、分支点数量、端点数量和总小胶质细胞交叉点的减少所证明的那样。ROF 还降低了离子化钙结合衔接分子 1 的表达和白细胞介素 1β 的水平。蛋白质印迹分析表明，PDE4 抑制抑制高迁移率组框 1 蛋白 (HMGB1)/RAGE 信号通路，如 HMGB1、RAGE、toll 样受体 4、磷酸化 p38 丝裂原活化蛋白激酶和核因子 κ 的水平在用 ROF 治疗后，小鼠海马和皮层的 -B 均降低。此外，ROF 还降低了 NLRP3 的蛋白质水平，NLRP3 是含有凋亡相关斑点样蛋白 (ASC) 和需要半胱氨酸的天冬氨酸蛋白酶 1 (Caspase-1)，它们是 NLRP-3 介导的炎性体信号通路中的关键蛋白。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有助于 PDE4 抑制剂的抗抑郁样作用。而且，ROF 具有作为治疗抑郁症的候选药物的潜力。