A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia
A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia
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DOI：
10.1523/jneurosci.1563-05.2005
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发表时间：
2005-07-06
影响因子：
5.3
通讯作者：
Lipton, SA
中科院分区：
文献类型：
--
作者：
Gu, ZZ;Cui, J;Lipton, SA
神经元细胞死亡发生在许多神经退行性疾病和中风期间。基质金属蛋白酶 (MMP)，尤其是 MMP-9 的异常、过度活性，直接导致神经元凋亡和脑损伤（Rosenberg 等，1996；Asahi 等，2001；Gu 等，2002；Horstmann 等，2003）。我们确定 MMP-9 会降解细胞外基质蛋白层粘连蛋白，并且这种降解会在小鼠短暂性局灶性脑缺血模型中诱导神经元凋亡。我们还确定，高度特异性的硫杂丙环明胶酶抑制剂 SB-3CT 可阻断 MMP-9 活性，包括 MMP-9 介导的层粘连蛋白裂解，从而挽救神经元免于凋亡。我们的结论是，MMP-9 是一个非常有前途的药物靶点，SB-3CT 衍生物对中风患者具有显着的治疗潜力。
Neuronal cell death occurs during many neurodegenerative disorders and stroke. The aberrant, excessive activity of matrix metalloproteinases (MMPs), especially MMP-9, contributes directly to neuron apoptosis and brain damage (Rosenberg et al., 1996; Asahi et al., 2001; Gu et al., 2002; Horstmann et al., 2003). We determined that MMP-9 degrades the extracellular matrix protein laminin and that this degradation induces neuronal apoptosis in a transient focal cerebral ischemia model in mice. We also determined that the highly specific thiirane gelatinase inhibitor SB-3CT blocks MMP-9 activity, including MMP-9-mediated laminin cleavage, thus rescuing neurons from apoptosis. We conclude that MMP-9 is a highly promising drug target and that SB-3CT derivatives have significant therapeutic potential in stroke patients.