Inhibition of MMP-9 by a selective gelatinase inhibitor protects neurovasculature from embolic focal cerebral ischemia.
Inhibition of MMP-9 by a selective gelatinase inhibitor protects neurovasculature from embolic focal cerebral ischemia.
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DOI：
10.1186/1750-1326-7-21
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发表时间：
2012-05-15
影响因子：
15.1
通讯作者：
Gu Z
中科院分区：
文献类型：
--
作者：
Cui J;Chen S;Zhang C;Meng F;Wu W;Hu R;Hadass O;Lehmidi T;Blair GJ;Lee M;Chang M;Mobashery S;Sun GY;Gu Z
脑缺血已被证明会诱导基质金属蛋白酶 (MMP) 激活，特别是 MMP-9，它与神经血管系统损伤有关，导致血脑屏障破坏、出血和神经变性。我们之前报道过，硫杂丙环抑制剂SB-3CT对明胶酶（MMP-2和-9）具有选择性，可以拮抗短暂性局灶性脑缺血后的神经元凋亡。在这里，我们使用富含纤维蛋白的凝块来闭塞大脑中动脉 (MCA)，并评估 SB-3CT 对神经血管系统的影响。结果表明，栓塞性缺血引起的神经行为缺陷和梗塞体积与微丝闭塞瞬时 MCA 模型引起的神经行为缺陷和梗塞体积相当。共聚焦显微镜显示栓子阻断了脑微血管和神经元细胞死亡。缺血后 SB-3CT 治疗减轻了梗塞体积，改善了神经行为结果，并拮抗了原体和活化 MMP-9 水平的增加。栓塞性缺血导致神经血管基质成分层粘连蛋白和紧密连接蛋白 ZO-1 降解、周细胞收缩以及凝集素阳性脑微血管丧失。尽管存在栓子，SB-3CT 减轻了这些结果并减少了出血量。有趣的是，连续 7 天的 SB-3CT 治疗可防止神经元层粘连蛋白降解，并保护神经元免受缺血性细胞死亡。这些结果表明硫杂丙环类选择性明胶酶抑制剂作为中风治疗的潜在治疗剂具有相当大的前景。
Cerebral ischemia has been shown to induce activation of matrix metalloproteinases (MMPs), particularly MMP-9, which is associated with impairment of the neurovasculature, resulting in blood–brain barrier breakdown, hemorrhage and neurodegeneration. We previously reported that the thiirane inhibitor SB-3CT, which is selective for gelatinases (MMP-2 and −9), could antagonize neuronal apoptosis after transient focal cerebral ischemia. Here, we used a fibrin-rich clot to occlude the middle cerebral artery (MCA) and assessed the effects of SB-3CT on the neurovasculature. Results show that neurobehavioral deficits and infarct volumes induced by embolic ischemia are comparable to those induced by the filament-occluded transient MCA model. Confocal microscopy indicated embolus-blocked brain microvasculature and neuronal cell death. Post-ischemic SB-3CT treatment attenuated infarct volume, ameliorated neurobehavioral outcomes, and antagonized the increases in levels of proform and activated MMP-9. Embolic ischemia caused degradation of the neurovascular matrix component laminin and tight-junction protein ZO-1, contraction of pericytes, and loss of lectin-positive brain microvessels. Despite the presence of the embolus, SB-3CT mitigated these outcomes and reduced hemorrhagic volumes. Interestingly, SB-3CT treatment for seven days protected against neuronal laminin degradation and protected neurons from ischemic cell death. These results demonstrate considerable promise for the thiirane class of selective gelatinase inhibitors as potential therapeutic agents in stroke therapy.