基于JNK/p53/SLC7A11信号通路探讨益肾健脑方对血管性痴呆大鼠神经细胞铁死亡的影响  

Effect of decoction for replenishing kidney and fortifying brain on neuronal ferroptosis in vascular dementia rats via JNK/p53/SLC7A11 signaling pathway

作　　者：何飘 汪辛强 陈亚[1] 胡国恒[1] 贺海霞[1] 雷华娟[1] 谢映 康蕾 HE Piao;WANG Xinqiang;CHEN Ya;HU Guoheng;HE Haixia;LEI Huajuan;XIE Ying;KANG Lei(The First Affiliated Hospital of Hunan University of Chinese Medicine,Changsha 410007,Hunan,China)

机构地区：[1]湖南中医药大学第一附属医院,湖南长沙410007

出　　处：《现代中西医结合杂志》2025年第1期10-17,共8页Modern Journal of Integrated Traditional Chinese and Western Medicine

基　　金：湖南省自然科学基金项目(2022JJ40334);国家自然科学基金青年基金项目(82104971);湖南省卫生健康委卫生科研课题(202203074417);湖南中医药管理局课题(C2023036);湖南中医药大学校级科研基金项目(2021XJJJ044,2024XYLH363);全国名老中医药专家胡国恒传承工作室建设项目(国中医药函人教函[2022]75号);湖南中医药大学中医学世界一流培育学科(2023)。

摘　　要：目的探讨益肾健脑方对血管性痴呆大鼠学习记忆能力、神经递质及神经细胞磷酸化氨基末端激酶(p-JNK)、磷酸化肿瘤抑制蛋白p53(p-p53)、溶质载体家族7成员11(SLC7A11)、核受体共激活因子4(NCOA4)表达的影响。方法取60只SD大鼠,随机选择10只作为假手术组,其余大鼠制备血管性痴呆模型。将造模成功大鼠随机分为模型组、多奈哌齐组及益肾健脑方低、中、高剂量组,每组7只。多奈哌齐组给予多奈哌齐0.45 mg/kg灌胃,益肾健脑方低、中、高剂量组分别给予益肾健脑方6.075 g/kg、12.15 g/kg、24.3 g/kg灌胃,模型组和假手术组给予等量蒸馏水灌胃。连续灌胃4周后,Morris水迷宫检测大鼠的学习记忆能力,TUNEL染色观察大脑皮质和海马CA1区神经细胞凋亡情况,免疫组化检测大脑皮质和海马CA1区多巴胺(DA)、5-羟色胺(5-HT)阳性表达情况,Western blot法检测海马组织中p-JNK、p-p53、SLC7A11、NCOA4蛋白表达情况。结果与假手术组比较,模型组大鼠学习记忆能力下降;大脑皮质和海马CA1区神经细胞排列稀疏,胞质空泡状;大脑皮质和海马CA1区神经细胞凋亡率均明显升高(P均<0.05),DA、5-HT阳性表达平均光密度均明显降低(P均<0.05);海马组织中p-JNK、p-p53、NCOA4蛋白相对表达量均明显升高(P均<0.05),SLC7A11蛋白相对表达量明显降低(P<0.05)。与模型组比较,各给药组大鼠学习记忆能力改善,大脑皮质和海马CA1区损伤减轻;大脑皮质和海马CA1区神经细胞凋亡率均明显降低(P均<0.05),DA、5-HT阳性表达平均光密度均明显升高(P均<0.05);海马组织中p-JNK、p-p53、NCOA4蛋白相对表达量均明显降低(P均<0.05),SLC7A11蛋白相对表达量均明显升高(P均<0.05),且益肾健脑方高剂量组上述各项指标改善情况均明显优于益肾健脑方低剂量组(P均<0.05)。结论益肾健脑方可以提高血管性痴呆大鼠学习记忆能力,减轻大脑皮质和海马CA1区损伤,抑制神经�Objective It is to explore the effects of decoction for replenishing kidney and fortifying brain(DRKFB)on learning and memory abilities in vascular dementia rats,as well as its effect on the expressions of phosphorylated c-Jun N-terminal kinase(p-JNK),p-P53,solute carrier family 7 member 11(SLC7A11),nuclear receptor coactivator 4(NCOA4)in neural cells.Methods Sixty SD rats were taken,in which 10 rats were randomly selected as the sham operation group,and the remaining rats were prepared as vascular dementia models.The successfully modeled rats were randomly divided into model group,donepezil group,and low,medium and high dose groups of Y DRKFB,with 7 rats in each group.The donepezil group was given donepezil 0.45 mg/kg by gavage,the low,medium and high dose groups of DRKFB were given DRKFB 6.075 g/kg,12.15 g/kg and 24.3 g/kg by gavage,respectively,the model group and sham operation group were given equal amount of distilled water by gavage.After 4 weeks of continuous gavage,the learning memory ability of rats was detected by Morris water maze,the apoptosis of neuronal cells in cerebral cortex and hippocampal CA1 area was observed by TUNEL staining,the positive expressions of dopamine(DA)and 5-hydroxytryptamine(5-HT)in cerebral cortex and hippocampal CA1 area were detected by immunohistochemistry,and the protein expressions of p-JNK,p-p53,SLC7A11 and NCOA4 in hippocampal tissue were detected by Western blot.Results Compared with the Sham operation group,the learning and memory ability of rats in the model group was decreased,the nerve cells in cerebral cortex and hippocampal CA1 area were sparsely arranged,the cytoplasm was vacuolated,the apoptosis of nerve cells in cerebral cortex and hippocampal CA1 area was increased,the mean optical densities of DA and 5-HT positive expression were significantly decreased(all P<0.05),the relative protein expressions of p-JNK,p-p53,and NCOA4 in hippocampal tissues were significantly increased(all P<0.05),and the relative protein expressions of SLC7A11 was significantly decrease

关 键 词：血管性痴呆 益肾健脑方 铁死亡 C-JUN氨基末端激酶 肿瘤抑制蛋白p53 溶质载体家族7成员11 神经递质 

分 类 号：R-332[医药卫生]