Matrix metalloproteinase-9 is elevated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in mice
Matrix metalloproteinase-9 is elevated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in mice
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DOI：
10.1385/nmm:5:2:119
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发表时间：
2004-01-01
影响因子：
3.5
通讯作者：
Beal, MF
中科院分区：
文献类型：
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作者：
Lorenzl, S;Calingasan, N;Beal, MF
基质金属蛋白酶（MMP）是能够降解细胞外基质组分的蛋白水解酶。最近的证据表明，基质金属蛋白酶在神经退行性疾病的发病机制，如阿尔茨海默病和肌萎缩侧索硬化症。在这项研究中，我们调查了MMP-9（明胶酶B）的参与1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）帕金森病小鼠模型，使用酶谱，免疫组织化学和蛋白质印迹分析。MMP-9的活性在MPTP注射后3 h在纹状体和24 h后在黑质中上调。虽然MMP-9的表达下降，在纹状体72小时，它仍然在黑质升高相比，对照组长达7天后MPTP管理。免疫组化结果显示，MPTP给药后，神经元和小胶质细胞是MMP-9表达的来源。用基于异羟肟酸的MMP抑制剂Ro 28-2653治疗显著减少了黑质延髓部的多巴胺消耗和酪氨酸羟化酶免疫反应性神经元的损失。MMP-9的表达，通过酶谱法测量在黑质MMP抑制剂减少。这些结果表明，MMP-9诱导后，MPTP应用在小鼠和MMPs的药理学抑制保护MPTP神经毒性。
Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading components of the extracellular matrix. Recent evidence has implicated MMPs in the pathogenesis of neurodegenerative diseases as Alzheimer's disease and amyotrophic lateral sclerosis. In this study, we investigated the involvement of MMP-9 (gelatinase B) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease using zymography, immunohistochemistry, and Western blot analysis. The activity of MMP-9 was upregulated at 3 h after MPTP injection in the striatum and after 24 h in the substantia nigra. Although MMP-9 expression decreased in the striatum by 72 h, it remained elevated in the substantia nigra compared to controls up to 7 d after MPTP administration. Immunohistochemistry showed that neurons and microglia are the source of MMP-9 expression after MPTP administration to mice. Treatment with a hydroxamate-based MMP inhibitor, Ro 28-2653 significantly reduced dopamine depletion and loss of tyrosine hydroxylase immunoreactive neurons in the substantia nigra pars compacta. MMP-9 expression as measured via zymography in the substantia nigra was reduced by the MMP inhibitor. These results indicate that MMP-9 is induced after MPTP application in mice and that pharmacologic inhibition of MMPs protects against MPTP neurotoxicity.