出 处:《西北药学杂志》2025年第2期70-79,共10页Northwest Pharmaceutical Journal
基 金:二〇二二年度河南省医学科技攻关计划项目(编号:202202131)。
摘 要:目的探讨瑞马唑仑(remimazolam,Re)对脑出血(intracerebral hemorrhage,ICH)大鼠学习记忆障碍的影响及机制。方法右侧尾状核注射胶原酶Ⅶ构建ICH大鼠模型。将大鼠随机分为假手术(Sham)组、ICH组和ICH联合Re组。ICH组和ICH联合Re组大鼠右侧尾状核内注射0.4 IU胶原酶Ⅶ,Sham组注射相同剂量的生理盐水。ICH联合Re组在胶原酶Ⅶ注射前1 h按20 mg·kg^(−1)剂量腹腔注射1次Re,然后,在胶原蛋白Ⅶ注射后每12 h注射1次Re。用Morris水迷宫实验评价大鼠的学习记忆能力,用神经功能评分评估大鼠神经功能缺损情况;干湿比评估脑水肿情况;冠状切片分析血肿大小;苏木素-伊红(hematoxylin&eosin,HE)染色和Nissl染色检测组织病理变化。用免疫荧光染色和蛋白质印迹法(Western blotting)检测相关蛋白的表达水平。酶联免疫吸附试验测定炎症因子的含量。末端脱氧核苷酸转移酶介导的dUTP缺口末端标记(terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling,Tunel)-神经特异核抗原(neurospecific nucleoprotein,NeuN)双免疫荧光染色和Fluoro-Jade C(FJC)染色分别评价神经元细胞凋亡和神经元退化情况。结果ICH术后24、72 h大鼠神经功能缺损和脑含水量均显著高于Sham组,Re可降低神经功能评分并降低脑含水量。Re可显著缩小ICH后3 d的脑血肿体积,减轻组织病理学损伤,并提高脑出血大鼠的学习记忆能力。ICH导致大鼠脑组织中离子钙结合适配器分子1(ionized calcium-binding adapter molecule-1,Iba-1)、髓过氧物酶(myeloperoxidase,MPO)阳性细胞数、Iba-1、MPO、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、白细胞介素(interleukin,IL)-1β和IL-6的表达水平及大鼠血清和脑脊液中TNF-α、IL-1β和IL-6的含量均显著增加,Re则可降低Iba-1、MPO、TNF-α、IL-1β和IL-6水平。此外,Re可显著降低ICH大鼠脑组织中FJC和Tunel阳性细胞数量及促凋亡蛋白B细胞淋巴瘤-2(B-cell lymphoma-2,BObjective To investigate the influence and mechanisms of remimazolam(Re)on learning and memory impairment in rats with intracerebral hemorrhage(ICH).Methods ICH rat model was constructed via injection collagenaseⅦinto the right caudate nucleus.The rats were randomly divided into 3 groups,Sham,ICH and ICH combined with Re.The rats in the ICH group and ICH combined with Re group received 0.4 IU collagenaseⅦin the right caudate nucleus,while the sham group rats were injected with an equal volume of normal saline.In the ICH combined with Re group,Re was intraperitoneally injected into rats at a dose of 20 mg·kg^(−1) 1 hour prior to collagenaseⅦinjection,and then once every 12 hours after collagenⅦinjection.Morris water maze was performed to evaluate the learning and memory capacity of rats,and neural function deficit was evaluated by neural function score.The dry-wet ratio was used to assess cerebral edema and coronal sections were used to analyze hematoma volume.The histopathological changes were detected by Hematoxylin&eosin(HE)and Nissl staining.Immunofluorescence staining and Western blotting were conducted to determine protein expressions and enzyme-linked immunosorbent assay was used to measure the levels of inflammatory factors.Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(Tunel)-neuro-specific nucleoprotein(NeuN)double immunofluorescence staining and Fluoro-Jade C(FJC)staining were used to evaluate the apoptosis and degeneration of neuronal cells.Results The neurological impairment and brain water content of rats were significantly higher than that in sham group 24 hours and 72 hours post-ICH operation,which were attenuated by Re treatment.Re significantly reduced hematoma volume and histopathological damage,and improved the learning and memory capacity on day 3 after ICH.ICH enhanced ionized calcium-binding adapter molecule-1(Iba-1)-and myeloperoxidase(MPO)-positive cells in brain tissues,as well as the expressions of Iba-1,MPO,tumor necrosis factor-α(TNF-α),interleukin(I
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