Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage
Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage
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DOI：
10.1093/brain/awh489
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发表时间：
2005-07-01
期刊：
影响因子：
14.5
通讯作者：
Tsirka, SE
中科院分区：
文献类型：
--
作者：
Wang, J;Tsirka, SE
脑出血是一种急性神经系统疾病，目前尚无有效的治疗方法。脑出血后急性脑损伤的机制尚不清楚。虽然少数研究表明明胶酶基质金属蛋白酶(MMP)-9在脑出血中起有害作用，但MMP-9活性与脑出血后急性脑损伤的关系尚不明确。在这项研究中，我们首先使用胶原酶诱导的脑出血小鼠模型检测明胶酶在体内的表达。凝胶酶谱分析显示，脑出血后MMP-9被激活并上调。原位酶谱分析显示，明胶酶活性主要与神经元和血管基质内皮细胞共定位。广谱金属蛋白酶抑制剂GM6001 （100 mg/kg）抑制可改善明胶酶活性失调、中性粒细胞浸润、氧化应激产生、脑水肿和神经元退化。功能改善和损伤体积减少也被观察到。我们提供的证据表明，MMP-9可能在脑出血后3天内的急性脑损伤中发挥有害作用。在这一关键时期阻断MMP活性可能作为治疗脑出血后急性脑损伤的有效治疗策略。
Intracerebral haemorrhage (ICH) is an acute neurological disorder without effective treatment. Mechanisms of acute brain injury after ICH remain to be clarified. Although a few studies suggested a detrimental role for the gelatinase matrix metalloproteinase (MMP)-9 in ICH, the relationship between MMP-9 activity and acute brain injury after ICH is not determined. In this study, we first examined the expression of gelatinases in vivo using a collagenase-induced mouse model of ICH. Gel zymography revealed that MMP-9 was activated and upregulated after ICH. In situ zymography showed that gelatinase activity was mostly co-localized with neurons and endothelial cells of the blood vessel matrix. Inhibition with a broad-spectrum metalloproteinase inhibitor GM6001 (100 mg/kg) ameliorated dysregulated gelatinase activity, neutrophil infiltration, production of oxidative stress, brain oedema and degenerating neurons. Functional improvement and a decrease in injury volume were also observed. We provide evidence that MMP-9 may play a deleterious role in acute brain injury within the first 3 days after ICH. Blockade of MMP activity during this critical period may have efficacy as a therapeutic strategy for the treatment of acute brain injury after ICH.