Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia
Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia
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DOI：
10.1523/jneurosci.4243-03.2004
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发表时间：
2004-01-21
影响因子：
5.3
通讯作者：
Lo, EH
中科院分区：
文献类型：
--
作者：
Lee, SR;Tsuji, K;Lo, EH
全脑缺血后海马神经元选择性死亡的机制尚不清楚。在这里，我们探讨了基质金属蛋白酶（MMPs）在这种现象中可能发挥的作用。虽然许多研究已经证明明胶酶MMP-9在局灶性脑缺血中的有害作用，但MMP蛋白水解失调如何影响全脑缺血还不太清楚。在这项研究中，CD-1小鼠进行短暂性全脑缺血。短暂闭塞颈总动脉20 ~ 40 min，3 d后海马神经元死亡增加。凝胶酶谱显示明胶酶（MMP-2和MMP-9）活性升高。原位酶谱显示，明胶酶活性主要与神经元特异性核蛋白染色的锥体神经元共定位。用广谱金属蛋白酶抑制剂BB-94（50 mg/kg，i. p.）在短暂的全脑缺血后显示出降低的海马明胶酶活性，并且与赋形剂处理的对照相比，海马神经元损伤显著降低（p < 0.01）。此外，与野生型小鼠相比，MMP-9基因敲除小鼠短暂全脑缺血后海马明胶酶活性和神经元损伤也显著降低（p < 0.05）。这些数据表明MMP-9在全脑缺血后海马迟发性神经元损伤的发病机制中具有潜在的有害作用。
Mechanisms of selective neuronal death in the hippocampus after global cerebral ischemia remain to be clarified. Here, we explored a possible role for matrix metalloproteinases (MMPs) in this phenomenon. Although many studies have demonstrated detrimental roles for the gelatinase MMP-9 in focal cerebral ischemia, how dysregulated MMP proteolysis influences global cerebral ischemia is less well understood. In this study, CD-1 mice were subjected to transient global ischemia. Transient occlusions of common carotid arteries for periods between 20 and 40 min led to increasing hippocampal neuronal death after 3 d. Gel zymography showed elevations in gelatinase (MMP-2 and MMP-9) activity. In situ zymography showed that gelatinase activity was mostly colocalized with neuron-specific nuclear protein-stained pyramidal neurons. Mice treated with the broad-spectrum metalloproteinase inhibitor BB-94 (50 mg/kg, i.p.) showed reduced hippocampal gelatinase activity after transient global cerebral ischemia and suffered significantly reduced hippocampal neuronal damage compared with vehicle-treated controls (p < 0.01). Additionally, hippocampal gelatinase activity and neuronal damage after transient global ischemia were also significantly reduced in MMP-9 knock-out mice compared with wild-type mice (p < 0.05). These data indicate a potential deleterious role for MMP-9 in the pathogenesis of delayed neuronal damage in the hippocampus after global cerebral ischemia.