摘要
目的以3×Tg-AD小鼠为AD模型,探究磷酸二酯酶4(phosphodiesterase 4,PDE4)抑制剂罗氟司特(roflumilast,Rof)对AD小鼠的改善作用,并对其机制进行初步探讨。方法将30只10月龄3×Tg-AD小鼠随机分为模型组、Rof高剂量组(5 mg·kg^(-1))、低剂量组(1 mg·kg^(-1)),并以野生型小鼠为对照组,各组连续灌胃给药30 d,通过行为学、病理检测及分子水平的检测,评估Rof对认知功能、Aβ沉积、Tau磷酸化、PDE4/cAMP/CREB信号通路及凋亡相关蛋白的影响。结果水迷宫和被动回避实验显示,与对照组相比,模型组小鼠认知功能明显降低,Rof治疗可改善其认知功能(P<0.05)。模型组小鼠神经元排列紊乱,尼氏体减少,Rof处理可减轻神经元损伤。分子结果显示,高剂量Rof可显著降低大脑皮质及海马中Aβ和磷酸化Tau蛋白的表达(P<0.05)同时,Rof上调了凋亡相关蛋白Bcl-2/Bax及神经营养因子BDNF的表达(P<0.05)。机制研究表明,模型组小鼠大脑皮质的PDE4A、PDE4B及海马的PDE4A、PDE4B、PDE4D均显著升高(P<0.05),高剂量Rof可明显降低上述3种PDE亚型的表达(P<0.05);同时,模型组小鼠大脑皮质及海马cAMP和pCREB/CREB表达下降(P<0.05),高剂量Rof可升高其水平(P<0.01)。结论Rof可逆转3×Tg-AD小鼠的认知功能障碍及病理学损伤,具有改善AD作用,可能与调控PDE4/cAMP/CREB信号通路相关。PDE4抑制剂可望用于治疗AD。
Aim This study aimed to evaluate the potential ameliorative effects of the phosphodiesterase 4(PDE4)inhibitor roflumilast(Rof)on cognitive function in the 3×Tg-AD mouse model of Alzheimer's disease(AD),while also exploring the underlying mechanisms.Methods Thirty ten-month-old 3×Tg-AD mice were randomly assigned to one of four groups:the model group,a high-dose Rof group(5 mg·kg^(-1)),a low-dose Rof group(1 mg·kg^(-1)),and a wild-type control group.All groups received oral gavage administration for 30 consecutive days.Behavioral assessments,histopathological evaluations,and molecular analyses were conducted to assess the effects of Rof on cognitive function,amyloid-beta(Aβ)deposition,Tau phosphorylation,the PDE4/cAMP/CREB signaling pathway,and apoptosis-related proteins.Results Water maze and passive avoidance tests revealed a significant decline in cognitive function in the model group compared to the control group,whereas Rof treatment significantly improved cognitive performance(P<0.05).Histopathological analysis demonstrated neuronal disarray and a reduction in Nissl bodies in the model group,while Rof treatment alleviated neuronal damage.Molecular analyses showed that high-dose Rof significantly reduced the expression of Aβand phosphorylated Tau in both the cerebral cortex and hippocampus(P<0.05).Furthermore,Rof upregulated the expression of apoptosisrelated proteins Bcl-2/Bax and the neurotrophic factor BDNF(P<0.05).Mechanistic studies indicated that the expression of PDE4A and PDE4B in the cortex,as well as PDE4A,PDE4B,and PDE4D in the hippocampus,was significantly elevated in the model group(P<0.05).High-dose Rof markedly reduced the expression of these three PDE4 subtypes(P<0.05).Moreover,the model group exhibited reduced levels of cAMP and pCREB/CREB in both the cortex and hippocampus(P<0.05),whereas high-dose Rof significantly increased these levels(P<0.01).Conclusion Rof effectively reversed cognitive dysfunction and pathological damage in 3×Tg-AD mice,demonstrating its therapeutic potential for Alzheimer's disease.These effects may be attributed to the modulation of the PDE4/cAMP/CREB signaling pathway.PDE4 inhibitors show promise as potential treatments for AD.
作者
赵璇
王琳
王丽宏
牛文辉
王浩
张汉霆
ZHAO Xuan;WANG Lin;WANG Li-hong;NIU Wen-hui;WANG Hao;ZHANG Han-ting(Institute of Pharmacology,Shandong First Medical University,Taian Shandong 271016,China;First People's Hospital of Jining City,Jining Shandong 272000,China;Chaoyang Campus of the 968th Hospital of the People's Liberation Army,Chaoyang Liaoning 122000,China;School of Pharmacy,Nanchang University,Nanchang 330019,China)
出处
《中国药理学通报》
北大核心
2026年第2期272-281,共10页
Chinese Pharmacological Bulletin
基金
国家自然科学基金资助项目(No 82073827)。
