8-型磷酸二酯酶抑制剂PF-04957325对冈田酸诱导阿尔茨海默病小鼠认知障碍的改善作用及机制  

Improvement and mechanism of PF-04957325,an 8-type phosphodiesterase inhibitor,in cognitive impairment induced by okadaic acid in mice with Alzheimer's disease

作　　者：吕玉丽 郭天洋 仇念壮 张汉霆 王浩 LYU Yu-li;GUO Tian-yang;QIU Nian-zhuang;ZHANG Han-ting;WANG hao(Institute of Pharmacology,Shandong First Medical University,Taian Shandong 271016,China;Dept of Pharmacology,School of Pharmacy,Qingdao University,Qingdao Shandong 266073,China)

机构地区：[1]山东第一医科大学药理学研究所,山东泰安271016 [2]青岛大学药学院药理教研室,山东青岛266073

出　　处：《中国药理学通报》2024年第9期1719-1726,共8页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 82073827)。

摘　　要：目的探讨磷酸二酯酶8(phosphodiesterase 8,PDE8)抑制剂PF-04957325对冈田酸(okadaic acid,OA)诱导阿尔茨海默病(Alzheimer's disease,AD)小鼠学习记忆、焦虑、抑郁的影响,并对其机制进行初步探讨。方法选取21只2月龄雄性C57BL/6J小鼠进行实验,随机分为对照组、AD模型组、PDE8抑制剂组(0.1 mg·kg^(-1))。模型组和PDE8抑制剂组小鼠双侧海马定位注射OA(每侧50 ng)诱导AD模型,注射OA 2 d后,PDE8抑制剂组给予0.1 mg·kg^(-1)抑制剂,AD模型组和对照组给予等剂量溶剂,共给药21 d。给予抑制剂d 13,对小鼠学习记忆能力及焦虑抑郁行为进行相关行为学检测,HE染色观察小鼠海马DG、CA1、CA3区神经细胞形态,Western blot检测小鼠海马内不同位点磷酸化Tau蛋白水平以及PDE8/cAMP/CREB通路相关蛋白的表达。结果与对照组相比,AD模型组Y迷宫轮替比、新物体识别指数、被动回避逃避潜伏期明显缩短(P<0.01),水迷宫穿越平台次数及在目标象限停留的时间减少(P<0.05),表现出学习记忆能力的下降,而给予PF-04957325可明显改善AD小鼠学习记忆能力;AD模型组进入旷场中央区次数及在中央区停留时间明显减少(P<0.05)、悬尾不动时间明显增加(P<0.01),提示小鼠有焦虑抑郁情况,给予PF-04957325后小鼠焦虑行为没有得到改善,对抑郁行为有一定改善;AD模型组小鼠海马DG、CA1、CA3区表现出核仁固缩、神经元排列不整齐,给予PF-04957325可缓解小鼠海马神经细胞的损伤。与对照组相比,AD模型组小鼠海马中Tau蛋白Ser199、Ser396和Ser202位点的磷酸化水平明显升高(P<0.01)、PDE8A及PDE8B蛋白表达量明显增加(P<0.01)、p-PKA/PKA和BDNF蛋白表达量降低(P<0.05),给予PF-04957325后Tau蛋白Ser396和Ser202位点的磷酸化水平明显降低(P<0.01)、PDE8A和PDE8B蛋白表达量明显降低(P<0.01)、p-PKA/PKA、p-CREB/CREB和BDNF蛋白表达量明显升高(P<0.01)。结论PDE8抑制剂PF-04957325能够提高AD小鼠的学习记Aim To investigate the effects of the phosphodiesterase 8(PDE8)inhibitor PF-04957325 on learning and memory,anxiety and depression in Alzheimer's disease(AD)mice induced by Okadaic acid(OA),and to explore its mechanism.Methods Twenty-one 2-month-old male C57BL/6J mice were selected for the experiment and randomly divided into the control group,AD model group,and PDE8 inhibitor group(0.1 mg·kg^(-1)).AD model was induced by bilateral hippocampal localization injection of OA(50 ng on each side)in the model and PDE8 inhibitor groups of mice.Two days after the injection of OA,PDE8 inhibitor group was given 0.1 mg·kg^(-1) drug,while the AD model groups and control group were given with the same volume of vehicle for 21 consecutive days.On day 13 of inhibitor administration,behavioral tests related to learning and memory abilities,anxiety and depressive behaviors were performed in mice.HE staining was used to observe the morphology of neuronal cells in the DG,CA1,and CA3 regions of the hippocampus of mice,and Western blot was used to detect the levels of phosphorylated Tau proteins at different sites within the hippocampus of mice as well as the expression of proteins related to the PDE8/cAMP/CREB pathway.Results Compared with the control group,the Y-maze Spontaneous alternation,Recognition index of NOR and Latency of PAT were significantly shorter(P<0.01),and Entries times、Time in the target quadrant of MWM were reduced(P<0.05)in the AD model group,which showed a decrease in the ability of learning and memory,whereas the administration of PF-04957325 significantly improved the ability of learning and memory in the AD mice;mice in the AD model group showed a significant decrease in the number of entries into the central area of the OFT and the time spent in the central area(P<0.05),and a significant increase in the Immobility time of TST(P<0.01),suggesting that the mice had anxiety and depression,and the administration of PF-04957325 did not improve the anxious behavior of the mice,but improved the depressed behavio

关 键 词：磷酸二酯酶 PDE8抑制剂 阿尔茨海默病 学习记忆 TAU蛋白 冈田酸 

分 类 号：R-332[医药卫生] R322.81R338.64R341R745.7R977.3