基于PGAM5-Drp1轴调控线粒体稳态探讨温肺降浊方对血管性痴呆模型大鼠的神经保护作用  

The neuroprotective effect of Wenfei Jiangzhuo formula on vascular dementia model rats based on regulation of mitochondrial homeostasis by PGAM5-Drp1 axis

作　　者：张鼎 胡芷涵 孙春英 朱晓东 李方存[1] 姜明贺 秦红玲[3] 陈炜[3] 胡跃强[3] ZHANG Ding;HU Zhi-han;SUN Chun-ying;ZHU Xiao-dong;LI Fang-cun;JIANG Ming-he;QIN Hong-ling;CHEN Wei;HU Yue-qiang(Graduate School,Guangxi University of Traditional Chinese Medicine,Nanning 530001,China;School of Pharmacy,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;Dept of Brain Diseases,the First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine,Nanning 530001,China)

机构地区：[1]广西中医药大学研究生院,广西南宁530001 [2]上海中医药大学药学院,上海201203 [3]广西中医药大学第一附属医院脑病一科,广西南宁530001

出　　处：《中国药理学通报》2024年第11期2158-2164,共7页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 82260904);广西中医脑病临床研究中心项目(No AD20238028);国家中医药管理局高水平重点学科-中医内科学(No ZYYZDXK-2023166);广西中医药大学“歧黄工程”高层次人才团队(No 202410);广西中医药重点学科建设项目(No GZXK-Z-20-13);广西中医药大学博士研究生创新项目(No YCBXJ2023010)。

摘　　要：目的观察温肺降浊方对血管性痴呆(vascular dementia,VaD)大鼠的影响,探究其可能的作用机制。方法36只健康雄性SD大鼠随机分为Sham group、Model group、Donepezil group、WFJZF-L group、WFJZF-M group和WFJZF-H group,每组6只,除Sham group,其余各组制备VaD模型,造模成功后各组以相应药物灌胃,治疗3周后进行各项检测。观察各组大鼠的行为学、海马CA1区形态学、神经树突及线粒体的变化,检测磷酸甘油酸变位酶5(phosphoglycerate mutase 5,PGAM5)、粒体动力相关蛋白(dynamics-related proteins1,Drp1)、神经萎缩相关蛋白1(opticatrophyprotein-1,OPA1)及相关蛋白的表达。结果与Sham group比较,Model group和各干预组大鼠逃避潜伏期延长(P<0.05),穿越平台次数缩短(P<0.05),海马神经元形态稀疏,二级树突棘减少,线粒体外膜破裂;海马组织中PGAM5、Drp1蛋白表达升高(P<0.05),OPA1、Mfn1/2蛋白表达下降(P<0.05);与Model group比较,Donepezil group和WFJZF-H group大鼠逃避潜伏期缩短(P<0.05),穿越平台次数增加(P<0.05),海马神经元数量增多,排列紧密,二级树突增多,线粒体损伤减少;PGAM5、Drp1蛋白表达下降(P<0.05),OPA1、Mfn1/2蛋白表达升高(P<0.05)。结论温肺降浊方可以调控PGAM5-Drp1信号轴以改善线粒体稳态平衡,从而改善大脑认知情况,发挥脑保护效应。Aim To observe the effects of Wenfei Jiangzhuo formula(WFJZF)on rats with vascular dementia and investigate its possible mechanism of action.Methods Thirty-six healthy male SD rats were randomly divided into the sham group,model group,donepezil group,and low-dose,medium-dose and high-dose groups of Wenfei Jiangzhuo formula,with six rats per group.Except for the sham group,the other groups were prepared as VaD models,and each group was gavaged with the corresponding drugs after successful modeling,and tests were performed after three weeks of treatment.Behavioral,hippocampal CA1 area morphology,neural dendrites and mitochondrial changes were observed in all groups of rats,and phosphoglycerate mutase 5(PGAM5),dynamics-related proteins1(Drp1),opticatrophyprotein-1(OPA1),and other proteins were detected in each group.Results Compared with the sham group,rats in the model group and each intervention group had prolonged escape latency(P<0.05),a shorter number of traversals across the platforms(P<0.05),a sparse morphology of hippocampal neurons,a reduction in the number of secondary dendritic spines,and a rupture of the outer membrane of the mitochondria;the expression of the PGAM5 and Drp1 proteins in hippocampal tissues was elevated(P<0.05),and the expression of the OPA1 and Mfn1/2 protein expression decreased(P<0.05);compared with the model group,donepezil group and Wenfei Jiangzhuo formula high-dose group of rats had shorter evasion latency(P<0.05),increased number of times to traverse the platform(P<0.05),increased number of hippocampal neurons,tightly packed,more secondary dendritic structures,and reduced mitochondrial damage;the expression of PGAM5 and Drp1 proteins was reduced(P<0.05),and the expression of OPA1 and Mfn1/2 proteins was elevated(P<0.05).Conclusions Wenfei Jiangzhuo formula can regulate the PGAM5-Drp1 signaling axis to improve the balance of mitochondrial homeostasis,thus improving the cognitive condition of the brain and exerting cerebroprotective effects.

关 键 词：温肺降浊方 PGAM5-Drp1轴 线粒体稳态 血管性痴呆 神经保护 

分 类 号：R285.5[医药卫生—中药学]