中药新药与临床药理2025，Vol.36Issue(9)：1413-1422,10.DOI:10.19378/j.issn.1003-9783.2025.09.001
丹蒌片调控铁死亡改善血管性痴呆大鼠认知功能的作用机制
Mechanism of Danlou Tablets in Improving Cognitive Function in Vascular Dementia Rats by Regulating Ferroptosis
摘要
Abstract
Objective To investigate the effects of Danlou Tablets on cognitive function in vascular dementia(VD)rats and its underlying mechanisms.Methods Ten SD rats were randomly selected as the sham-operated group,while 50 rats underwent bilateral common carotid artery occlusion(BCCAO)to establish the VD model.Successfully modeled rats were randomly divided into the model group,low-dose Danlou Tablets group(0.4 g·kg-1),high-dose Danlou Tablets group(0.8 g·kg-1),and Donepezil Hydrochloride group(0.45 mg·kg-1),with 10 rats per group.All groups received intragastric administration(10 mL·kg-1)once daily for 8 weeks.Behavioral tests(Morris water maze,Y-maze)were conducted to assess learning,memory,and spatial exploration abilities.Hippocampal neuronal structure was examined via hematoxylin-eosin(HE)staining;iron deposition in the hippocampus and cortex was evaluated using Prussian blue staining;ultrastructural changes in hippocampal neurons,synapses,and mitochondria were observed via transmission electron microscopy(TEM).Brain tissue levels of Fe2+,Fe3+,glutathione(GSH),and malondialdehyde(MDA)were quantified.Western Blot measured hippocampal protein expression of transferrin receptor 1(TfR1),ferroportin 1(FPN1),ferritin heavy chain 1(FTH1),and glutathione peroxidase 4(GPX4).Immunohistochemistry assessed FTH1 expression in the hippocampus.Results Compared with the sham group,the model group exhibited significantly prolonged escape latency(days 3-5,P＜0.01),reduced target quadrant dwell time and platform crossings(P＜0.01),unchanged total arm entries(P＞0.05),and decreased spontaneous alternation accuracy(P＜0.01).Neurons were disorganized,with widened intercellular gaps,nuclear pyknosis,fragmentation,and vacuolation;interstitial edema and"fracture zones"were observed.Iron deposition(brown/yellow-positive cells)increased markedly.TEM revealed sparse organelles,marginated heterochromatin,blurred membranes,reduced synaptic vesicles,widened synaptic clefts(P＜0.01),and damaged mitochondria(swelling,cristae disruption).Fe2+,Fe3+,and MDA levels rose(P＜0.01),while GSH declined(P＜0.01).Hippocampal TfR1 protein expression increased(P＜0.05),whereas FPN1,GPX4,and FTH1 protein expression decreased(P＜0.01).FTH1 immunoreactivity weakened(P＜0.01).Compared with the model group,all treatment groups showed shortened escape latency(P＜0.05,P＜0.01),improved target quadrant dwell time and platform crossings(P＜0.05),unchanged total arm entries(P＞0.05),and elevated alternation accuracy(P＜0.05).Neuronal arrangement normalized,with reduced edema and iron deposition(P＜0.01).TEM demonstrated restored organelles,centralized nuclei,narrower synaptic clefts(P＜0.01),and intact mitochondrial cristae.Fe2+,Fe3+,and MDA levels declined(P＜0.01),while GSH rose(P＜0.01).TfR1 protein expression decreased(P＜0.01),whereas protein expression of FPN1,GPX4,and FTH1 increased(P＜0.05,P＜0.01).FTH1 protein expression was significantly upregulated in the hippocampus,and the average optical density value was significantly increased(P＜0.01).Conclusion Danlou Tablets ameliorates cognitive dysfunction and hippocampal neuronal damage in VD rats,potentially by inhibiting iron-dependent oxidative stress and subsequent ferroptosis.关键词
丹蒌片/血管性痴呆/认知功能障碍/铁死亡/氧化应激/大鼠Key words
Danlou Tablets/vascular dementia/cognitive dysfunction/ferroptosis/oxidative stress/rats分类
医药卫生引用本文复制引用
张雅涵,高爱社,田浩,任金玲,曹珊,陈芳,宋军营,张妍..丹蒌片调控铁死亡改善血管性痴呆大鼠认知功能的作用机制[J].中药新药与临床药理,2025,36(9):1413-1422,10.基金项目
中国博士后科学基金项目(2023M741089) （2023M741089）
河南省科技攻关项目(232102310434) （232102310434）
河南省自然科学基金面上项目(242300421295) （242300421295）
河南省高等学校重点科研项目(24A310004). （24A310004）
