脑水肿的发病机理及药物治疗-1.pptx

1、脑水肿的发病机理及药物治疗,医院及讲者信息,脑水肿,脑实质聚集过量液体,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,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,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,The Cold Injury Model,Cold injury is performed byinflicting freeze stimulation on the hemisphere o

2、f 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,The Fluid Percussion Injury(FPI)Model,Fluid percussion injury is performed by an injury to the intact dura after cranie

3、ctomy 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；,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

4、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,The Water Intoxication Model,induces a relative decrease of extracellular Na+concentration，best reflects simulation of hyponatremiaproduced by intraperitoneal loading of excessive distilled water corresponding to 10%40%of the body weight of experimental animalsadopted

5、as a model of cytotoxic edema.,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,评估脑水肿方法,干湿称重法重量法MRI检测法,Wet-Dry Weight Method,a common and simple methodinvasive and not

6、performed in patientsbased on the weight measurement of brain tissue before and after complete dehydrationWater content(%)=100(wet weight dry weight)/wet weightWater content=(wet weight dry weight)/dry weight Tissue swelling(%)=100(final wet weight initial wet weight)/initial wet weightwet weight：Th

7、e weight before dehydrationdry weight：the weight after dehydration,The Gravimetric Method,The gravimetric technique is based on calculating the percentage of water from measuring the density of the tissue in experimental animalsThis method is also invasive and not performed in patientsAdvantages:hig

8、her sensitivityuse of smaller pieces of tissue,Magnetic Resonance Imaging(MRI),a noninvasive method，used for evaluating brain edema in patients and experimental animalsTwo Index:apparent diffusion coefficient（ADC）reduced ADC values correlate with cytotoxic edemaT2 imagingthe increased T2 values refl

9、ect the development of vasogenic edema,脑水肿关键因子及治疗,VEGF、MMPs、AQPs、NKCC1、ETB-R、GR,脑水肿生成关键因子,抗水肿治疗药物,麦通纳作用机制,作用与GCR/NFB 信号通路，抗炎作用上调GC受体表达，抑制 NFB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 6:419-422,20132，Mol Pharmacol.201

10、0 May;77(5):818-273，J Zhejiang Univ Sci B.2005 Jan;6(1):28-324，Arzneimittelforschung.1970 May;20(5):699-7035，Yao Xue Xue Bao.2004 Jun;39(6):419-23.,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（4.0

11、mg/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,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,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,