脑水肿的发病机理及药物治疗课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2021/3/11 Thursday,脑水肿的发病机理及药物治疗,#,脑水肿的发病机理及药物治疗,医院及讲者信息,1,脑水肿的发病机理及药物治疗,脑水肿的发病机理及药物治疗医院及讲者信息1脑水肿的发病机理及,脑水肿,颅脑损伤,脑出血,脑梗等,脑水肿,颅内压升高,脑血流量下降、缺氧、脑疝,神经功能不可逆损伤、甚至死亡,脑实质聚集过量液体,2,脑水肿的发病机理及药物治疗,脑水肿颅脑损伤脑水肿颅内压升高脑血流量下降、缺氧、脑疝神经功,脑水肿分类,血管源性脑水肿,血脑屏障受损所致，大量液体和血管内蛋白质积聚于脑白质细胞间隙,常见于脑创伤、脑出血、脑缺血的第二阶段,3,脑水肿的发病机理及药物治疗,脑水肿分类血管源性脑水肿3脑水肿的发病机理及药物治疗,脑水肿分类,细胞毒性脑水肿,ATP,失功、细胞内外,Na+,转运失衡所致,水肿液分布于脑细胞内，细胞间隙不但不扩大，反而缩小,常见于脑缺血和肝衰,4,脑水肿的发病机理及药物治疗,脑水肿分类细胞毒性脑水肿4脑水肿的发病机理及药物治疗,脑水肿动物实验模型,冻伤模型,液压冲击伤模型,脑出血模型,水中毒模型,肝损模型,5,脑水肿的发病机理及药物治疗,脑水肿动物实验模型冻伤模型5脑水肿的发病机理及药物治疗,The Cold Injury Model,Cold injury is performed by,inflicting freeze stimulation on the hemisphere of the skull of the animal,After cold injury,BBB disruption is indicated by evaluating extravasation of Evans blue dye,冻伤模型,主要用于血管源性脑水肿的试验模型,冻伤直接破坏血管细胞，导致不可逆的血脑屏障损伤,特点：试验的可重复性及受伤面积的准确性,6,脑水肿的发病机理及药物治疗,The Cold Injury ModelCold inju,The Fluid Percussion Injury(FPI)Model,Fluid percussion injury is performed by an injury to the intact dura after craniectomy by impacts of rapidly pushed fluid(B1,B2).,As well as cold injury,the extravasation of Evans blue dye is observed(B3).,液压冲击伤模型,模拟脑创伤引发的脑水肿,可诱导各种降解酶如,MMP-9,的激活，导致血管基底膜的降解,可观察到炎性介质的增加及巨噬细胞的浸润；,7,脑水肿的发病机理及药物治疗,The Fluid Percussion Injury(F,The Cerebral Hemorrhage Model,通过脑实质内注射胶原蛋白酶破坏血管基底膜或者注射自体血制备脑出血模型（,ICH model,）,常见的蛛网膜下腔出血模型（,SAH model,）包括：单侧出血、双侧出血、血管内穿刺模型,可同时观察到血管源性脑水肿及细胞毒性脑水肿,initial hemorrhage,disturbance of neuronal and glial functions,glutamate release,membrane depolarization,mitochondrial dysfunction,cellular swelling,BBB breakdown,BBB dysfunction,thrombin and hemoglobin extravasation,inflammatory responses,8,脑水肿的发病机理及药物治疗,The Cerebral Hemorrhage Model通,The Water Intoxication Model,induces a relative decrease of extracellular Na,+,concentration,，,best reflects simulation of hyponatremia,produced by intraperitoneal loading of excessive distilled water corresponding to 10%40%of the body weight of experimental animals,adopted as a model of cytotoxic edema.,9,脑水肿的发病机理及药物治疗,The Water Intoxication Modelin,The Liver Failure Model,急性或慢性肝细胞失功引发的肝衰会诱导肝性脑病，造成中枢神经组织严重失功。,急、慢性肝衰导致的脑水肿发病机制不同,急性肝衰，,ICP,上升；慢性肝衰很少观察到,ICP,上升,肝衰模型产生的脑水肿为细胞毒性脑水肿,星形细胞肿胀,血脑屏障未见损害,一般采用硫代乙酰胺诱导肝细胞损伤,氨基半乳糖诱导急性肝衰,胆管结扎或门腔静脉吻合术诱导慢性肝衰,10,脑水肿的发病机理及药物治疗,The Liver Failure Model急性或慢性肝细,评估脑水肿方法,干湿称重法,重量法,MRI,检测法,11,脑水肿的发病机理及药物治疗,评估脑水肿方法干湿称重法11脑水肿的发病机理及药物治疗,Wet-Dry Weight Method,a common and simple method,invasive and not performed in patients,based on the weight measurement of brain tissue before and after complete dehydration,Water content(%)=100(wet weight dry weight)/wet weight,Water content=(wet weight dry weight)/dry weight,Tissue swelling(%)=100(final wet weight initial wet weight)/initial wet weight,wet weight,：,The weight before dehydration,dry weight,：,the weight after dehydration,12,脑水肿的发病机理及药物治疗,Wet-Dry Weight Methoda common,The Gravimetric Method,The gravimetric technique is based on calculating the percentage of water from measuring the density of the tissue in experimental animals,This method is also invasive and not performed in patients,Advantages:,higher sensitivity,use of smaller pieces of tissue,13,脑水肿的发病机理及药物治疗,The Gravimetric MethodThe grav,Magnetic Resonance Imaging(MRI),a noninvasive method,，,used for evaluating brain edema in patients and experimental animals,Two Index:,apparent diffusion coefficient,（,ADC,）,reduced ADC values correlate with cytotoxic edema,T2 imaging,the increased T2 values reflect the development of vasogenic edema,14,脑水肿的发病机理及药物治疗,Magnetic Resonance Imaging(MR,脑水肿关键因子及治疗,VEGF,、,MMPs,、,AQPs,、,NKCC1,、,ETB-R,、,GR,15,脑水肿的发病机理及药物治疗,脑水肿关键因子及治疗VEGF、MMPs、AQPs、NKCC1,脑水肿生成关键因子,16,脑水肿的发病机理及药物治疗,脑水肿生成关键因子16脑水肿的发病机理及药物治疗,抗水肿治疗药物,作用靶点,药物分类,抗水肿类型,VEGF,VEGF,抑制剂；,VEGF,受体拮抗剂；,血管源性脑水肿,MMPs,MMPs,抑制剂；,血管源性脑水肿,AQPs,AQ4,抑制剂；,AQ4,激动剂,细胞毒性脑水肿,血管源性脑水肿,NKCC1,Bumetanide,（布美他尼）,细胞毒性脑水肿,SUR1-regulated NCCa-ATP,Glibenclamide,格列本脲,细胞毒性脑水肿,ETB-R,ETB-R,拮抗剂,血管源性脑水肿,糖皮质激素受体,地塞米松,七叶皂苷钠,血管源性脑水肿,17,脑水肿的发病机理及药物治疗,抗水肿治疗药物作用靶点药物分类抗水肿类型VEGFVEGF抑制,麦通纳作用机制,作用与,GCR/NF,B,信号通路，抗炎作用,上调,GC,受体表达，抑制,NF,B,的活化,1,2,抑制,TNF-,IL-1,等炎症因子的产生,3,封闭毛细血管，减少毛细血管壁上小孔的数量和直径,4,维持正常血管通透性,抑制局部炎症细胞渗出,提高,SOD,活性，清除氧自由基,5,1,，,EXPERIMENTAL AND THERAPEUTIC MEDICINE 6:419-422,2013,2,，,Mol Pharmacol.2010 May;77(5):818-27,3,，,J Zhejiang Univ Sci B.2005 Jan;6(1):28-32,4,，,Arzneimittelforschung.1970 May;20(5):699-703,5,，,Yao Xue Xue Bao.2004 Jun;39(6):419-23.,18,脑水肿的发病机理及药物治疗,麦通纳作用机制作用与GCR/NFB 信号通路，抗炎作用1,麦通纳显著提高糖皮质激素受体的表达,脂多糖,(LPS),诱导的炎症小鼠模型中，,GR,蛋白水平表达显著下降（,p0.05),；,麦通纳显著提高,GR,蛋白的表达，不仅在麦通纳组，且在脂多糖,+,麦通纳组,GR,蛋白水平显著高于对照组（,p0.01),a,对照组；,b,麦通纳钠组（,3.6mg/kg);c,LPS,组；,d,地塞米松（,4.0mg/kg,）,+LPS,组；,f,麦通纳（,1.8mg/kg)+LPS,组,;g,麦通纳（,3.6mg/kg)+LPS,组,N.Jiang et al./Phytomedicine 18(2011)1276 1284,19,脑水肿的发病机理及药物治疗,麦通纳显著提高糖皮质激素受体的表达脂多糖(LPS)诱导的炎症,麦通纳协同激素抗炎消肿,低剂量可的松、麦通纳联合给药,6h,，水肿显著减轻,N.Jiang et al./Phytomedicine 18(2011)1276 1284,20,脑水肿的发病机理及药物治疗,麦通纳协同激素抗炎消肿低剂量可的松、麦通纳联合给药6h，水肿,总结,脑水肿是常见的中枢神经系统病理改变，可形成脑疝等严重并发症,现有的对症治疗药物（甘露醇等渗透性脱水剂）作用有限，需要开发新的抗水肿药物,脑水肿动物试验模型帮助了解脑水肿发病机制，发现影响关键因子，筛选有效抗水肿药物,麦通纳提高糖皮质激素受体表达，抗炎消肿