Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai'an, China.
Departments of Neuroscience and Behavioral Medicine & Psychiatry, the Rockefeller Neuroscience Institute, West Virginia University Health Sciences Center, Morgantown, West Virginia.
Int J Neuropsychopharmacol. 2020 Dec 10;23(10):700-711. doi: 10.1093/ijnp/pyaa048.
Depression is highly related to Alzheimer's disease (AD), yet no effective treatment is available. Phosphodiesterase-4 (PDE4) has been considered a promising target for treatment of AD and depression. Roflumilast, the first PDE4 inhibitor approved for clinical use, improves cognition at doses that do not cause side effects such as emesis.
Here we examined the effects of roflumilast on behavioral dysfunction and the related mechanisms in APPswe/PS1dE9 transgenic mice, a widely used model of AD. Mice at 10 months of age were examined for memory in the novel object recognition and Morris water-maze tests and depression-like behavior in the tail-suspension test and forced swimming test before killing for neurochemical assays.
In the novel object recognition and Morris water-maze, APPswe/PS1dE9 mice showed significant cognitive declines, which were reversed by roflumilast at 5 and 10 mg/kg orally once per day. In the tail-suspension test and forced swimming test, the AD mice showed prolonged immobility time, which was also reversed by roflumilast. In addition, the staining of hematoxylin-eosin and Nissl showed that roflumilast relieved the neuronal cell injuries, while terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling analysis indicated that roflumilast ameliorated cell apoptosis in AD mice. Further, roflumilast reversed the decreased ratio of B-cell lymphoma-2/Bcl-2-associated X protein and the increased expression of PDE4B and PDE4D in the cerebral cortex and hippocampus of AD mice. Finally, roflumilast reversed the decreased levels of cyclic AMP (cAMP) and expression of phosphorylated cAMP response element-binding protein and brain derived neurotrophic factor in AD mice.
Together, these results suggest that roflumilast not only improves learning and memory but also attenuates depression-like behavior in AD mice, likely via PDE4B/PDE4D-mediated cAMP/cAMP response element-binding protein/brain derived neurotrophic factor signaling. Roflumilast can be a therapeutic agent for AD, in particular the comorbidity of memory loss and depression.
抑郁症与阿尔茨海默病（AD）高度相关，但目前尚无有效的治疗方法。磷酸二酯酶 4（PDE4）已被认为是治疗 AD 和抑郁症的有希望的靶点。罗氟司特是第一个被批准用于临床的 PDE4 抑制剂，在不引起呕吐等副作用的剂量下改善认知。
在这里，我们研究了罗氟司特对 APPswe/PS1dE9 转基因小鼠（一种广泛使用的 AD 模型）行为功能障碍及相关机制的影响。在杀死用于神经化学测定之前，用新颖物体识别和 Morris 水迷宫测试检查 10 个月大的小鼠的记忆，并用悬尾和强迫游泳测试检查抑郁样行为。
在新颖物体识别和 Morris 水迷宫中，APPswe/PS1dE9 小鼠表现出明显的认知能力下降，而罗氟司特以 5 和 10 mg/kg 每天口服一次可逆转这种下降。在悬尾和强迫游泳测试中，AD 小鼠的不动时间延长，而罗氟司特也可逆转这种情况。此外，苏木精-伊红和尼氏染色显示罗氟司特减轻了神经元细胞损伤，而末端脱氧核苷酸转移酶介导的 dUTP-生物素 nick-end 标记分析表明罗氟司特改善了 AD 小鼠的细胞凋亡。此外，罗氟司特逆转了 AD 小鼠大脑皮层和海马中 B 细胞淋巴瘤-2/Bcl-2 相关 X 蛋白的降低比例和磷酸化 cAMP 反应元件结合蛋白和脑源性神经营养因子的表达增加。最后，罗氟司特逆转了 AD 小鼠中环腺苷酸（cAMP）水平的降低和磷酸化 cAMP 反应元件结合蛋白和脑源性神经营养因子表达的降低。
总之，这些结果表明，罗氟司特不仅改善了 AD 小鼠的学习和记忆，而且减轻了抑郁样行为，可能通过 PDE4B/PDE4D 介导的 cAMP/cAMP 反应元件结合蛋白/脑源性神经营养因子信号通路。罗氟司特可以成为 AD 的治疗药物，特别是记忆丧失和抑郁共病的治疗药物。
