The biological cascade of second messenger–cyclic adenosine monophosphate (cAMP) –as a molecular mechanism implicated in memory and learning regulation has captured the attention of neuroscientists worldwide. cAMP triggers its foremost effector, protein kinase A (PKA), resulting in the activation of innumerable downstream targets. Roflumilast (ROF), a phosphodiesterase 4 inhibitor, has demonstrated a greater efficiency in enhancing cAMP signaling in various neurological disorders. This study was conducted to identify various downstream targets of PKA as mechanistic tools through which ROF could hinder the progressive cognitive impairment following central streptozotocin (STZ) administration in mice. Animals were injected with STZ (3 mg/kg/i.c.v) once. Five hours later, mice received ROF (0.4 mg/kg) with or without the PKA inhibitor, H89, for 21 days. ROF highly preserved the structure of hippocampal neurons. It improved the ability of mice to develop short-term memories and retrieve spatial memories in Y-maze and Morris water maze tests, respectively. ROF enhanced the gene expression of ABCB1 transporters and pregnane X receptors (PXR), and hampered Aβ accumulation in hippocampus. Simultaneously, it interfered with the processes of tau phosphorylation and nitration. This effect was associated with an upsurge in hippocampal arginase activity as well as a decline in glycogen synthase kinase-3β activity, nitric oxide synthase (NOS) activity, and inducible NOS expression. Contrariwise, ROF's beneficial effects were utterly abolished by co-administration of H89. In conclusion, boosting PKA, by ROF, modulated PXR/ABCB1 expression and arginase/NOS activities to restrict the main post-translational modifications of tau, Aβ deposition and, accordingly, cognitive deterioration of sporadic Alzheimer's disease.

第二信使——环磷酸腺苷 (cAMP) 的生物学级联反应——作为一种与记忆和学习调节有关的分子机制，引起了全世界神经科学家的关注。cAMP 触发其最重要的效应物蛋白激酶 A (PKA)，从而激活无数下游靶标。罗氟司特 (ROF) 是一种磷酸二酯酶 4 抑制剂，已证明在增强各种神经系统疾病中的 cAMP 信号传导方面具有更高的效率。本研究旨在确定 PKA 的各种下游目标作为机械工具，通过这些工具，ROF 可以阻碍小鼠中枢链脲佐菌素 (STZ) 给药后的进行性认知障碍。给动物注射一次 STZ (3 mg/kg/icv)。五小时后，小鼠接受 ROF (0.4 mg/kg)，有或没有 PKA 抑制剂 H89，21天。ROF高度保留了海马神经元的结构。它分别提高了小鼠在 Y 迷宫和莫里斯水迷宫测试中发展短期记忆和检索空间记忆的能力。ROF 增强了 ABCB1 转运蛋白和孕烷 X 受体 (PXR) 的基因表达，并阻碍了海马中 Aβ 的积累。同时，它干扰了 tau 的磷酸化和硝化过程。这种效应与海马精氨酸酶活性的升高以及糖原合酶激酶 3β 活性、一氧化氮合酶 (NOS) 活性和诱导型 NOS 表达的下降有关。相反，ROF 的有益效果被 H89 的共同给药完全消除。总之，通过 ROF 提升 PKA，