Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat
Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat
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DOI：
10.1212/wnl.48.4.921
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发表时间：
1997-04-01
期刊：
影响因子：
9.9
通讯作者：
Navratil, M
中科院分区：
文献类型：
--
作者：
Rosenberg, GA;Navratil, M
临床恶化通常发生在脑出血后1 - 2天。金属蛋白酶对细胞外基质的蛋白水解作用可能是一个影响因素，金属蛋白酶攻击基底膜并打开血脑屏障。基质金属蛋白酶和纤溶酶原激活物在细菌胶原酶诱导的脑出血后16至24小时增加，这表明阻断金属蛋白酶的药物可以减轻出血后的脑肿胀。因此，我们在大鼠脑内注射0.2、0.3、0.4或0.5单位的细菌胶原酶，以产生脑内出血。24小时后，取出脑组织用于测量脑水和电解质。用酶谱法测定蛋白酶。在胶原酶损伤后6小时开始用基质金属蛋白酶抑制剂BB-1101治疗，此时血肿形成，继发性水肿增加。细菌胶原酶在注射部位引起剂量依赖性血肿，在两个后部区域继发性脑水肿。较低的细菌胶原酶剂量（0.2和0.3单位）主要引起注射部位周围组织的脑水肿，而较高剂量（0.4和0.5单位）也影响对侧半球。给予BB-1101显著降低了具有0.4单位损伤的大鼠中远离注射部位的区域的脑水和钠含量（p < 0.05）。酶谱显示在24小时时92-kDa IV型胶原酶和尿激酶型纤溶酶原激活剂增加。蛋白水解级联酶抑制剂可用于治疗脑出血继发性脑水肿。
Clinical worsening often occurs 1 to 2 days after an intracerebral hemorrhage. Extracellular matrix proteolysis by metalloproteinases, which attack the basal lamina and open the blood-brain barrier, may be one contributing factor. Matrix metalloproteinases and plasminogen activators are increased 16 to 24 hours after a bacterial collagenase-induced intracerebral hemorrhage, suggesting that agents that block metalloproteinases may reduce the brain swelling after hemorrhage. Therefore, we injected 0.2, 0.3, 0.4, or 0.5 units bacterial collagenase intracerebrally in rats to produce an intracerebral hemorrhage. Twenty-four hours later, brain tissue was removed for measurement of brain water and electrolytes. Proteases were assayed by zymography. Treatment with a matrix metalloproteinase inhibitor, BB-1101, was begun 6 hours after the collagenase lesion, when the hematomas were formed and the secondary edema was increasing. Bacterial collagenase caused a dose-dependent hematoma at the injection site with secondary brain edema in both posterior regions. The lower bacterial collagenase doses (0.2 and 0.3 units) mainly caused brain edema in the tissue around the injection site, whereas the higher doses (0.4 and 0.5 units) also affected the opposite hemisphere. Administration of BB-1101 significantly reduced the brain water and sodium contents in regions away from the injection site in rats with 0.4 unit lesions (p < 0.05). Zymography showed an increase in 92-kDa type IV collagenase and urokinase-type plasminogen activator at 24 hours. Inhibitors of proteolytic cascade enzymes may be useful in treatment of secondary brain edema in intracerebral hemorrhage.