Phosphodiesterase 4 (PDE4) inhibitors have been shown to present beneficial effects in cerebral ischemic injury because of their ability to improve cognition and target different phases and mechanisms of cerebral ischemia, including apoptosis, neurogenesis, angiogenesis, and inflammation. The present study investigated whether repeated treatment with the PDE4 inhibitor roflumilast rescued memory loss and attenuated neuroinflammation in rats following transient global cerebral ischemia (TGCI). TGCI caused memory impairments, neuronal loss (reflected by Neuronal nuclei (NeuN) immunoreactivity), and compensatory neurogenesis (reflected by doublecortin (DCX) immunoreactivity) in the hippocampus. Also, increases in the protein expression of the phosphorylated response element‐binding protein (pCREB) and inflammatory markers such as the glial fibrillary acidic protein (GFAP) and ionized calcium‐binding adaptor molecule 1 (Iba‐1), were detected in the hippocampus in TGCI rats. Repeated treatment with roflumilast (0.003 and 0.01 mg/kg) prevented spatial memory deficits without promoting hippocampal protection in ischemic animals. Roflumilast increased the levels of pCREB, arginase‐1, interleukin (IL) 4, and IL‐10 in the hippocampus 21 days after TGCI. These data suggest a protective effect of roflumilast against functional sequelae of cerebral ischemia, which might be related to its anti‐inflammatory properties.

中文翻译：

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罗氟司特可预防短暂性全脑缺血后的空间记忆障碍并发挥抗炎作用

磷酸二酯酶4（PDE4）抑制剂已显示出对脑缺血损伤的有益作用，因为它们能够提高认知能力并靶向脑缺血的不同阶段和机制，包括凋亡，神经发生，血管生成和炎症。本研究调查了在短暂性全脑缺血（TGCI）后，PDE4抑制剂罗氟司特的重复治疗是否能挽救大鼠的记忆力丧失和神经炎症。TGCI在海马中引起记忆障碍，神经元丢失（由神经元核（NeuN）免疫反应所反映）和代偿性神经发生（由双皮质素（DCX）免疫反应所反映）。还，在TGCI的海马中检测到磷酸化反应元件结合蛋白（pCREB）和炎症标记物如胶质纤维酸性蛋白（GFAP）和离子化钙结合适配器分子1（Iba-1）的蛋白表达增加大鼠。罗氟司特（0.003和0.01 mg / kg）的重复治疗可防止空间记忆缺陷，而不会促进缺血动物的海马保护。罗氟司特在TGCI后21天增加了海马中pCREB，精氨酸酶-1，白介素（IL）4和IL-10的水平。这些数据表明罗氟司特对脑缺血的功能性后遗症有保护作用，这可能与其抗炎特性有关。罗氟司特（0.003和0.01 mg / kg）的重复治疗可防止空间记忆缺陷，而不会促进缺血动物的海马保护。罗氟司特在TGCI后21天增加了海马中pCREB，精氨酸酶-1，白介素（IL）4和IL-10的水平。这些数据表明罗氟司特对脑缺血的功能性后遗症有保护作用，这可能与其抗炎特性有关。罗氟司特（0.003和0.01 mg / kg）的重复治疗可防止空间记忆缺陷，而不会促进缺血动物的海马保护。罗氟司特在TGCI后21天增加了海马中pCREB，精氨酸酶-1，白介素（IL）4和IL-10的水平。这些数据表明罗氟司特对脑缺血的功能性后遗症具有保护作用，这可能与其抗炎特性有关。