The matrix metalloproteinases inhibitor Ro 26-2853 extends survival in transgenic ALS mice
The matrix metalloproteinases inhibitor Ro 26-2853 extends survival in transgenic ALS mice
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DOI：
10.1016/j.expneurol.2006.01.026
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发表时间：
2006-07-01
影响因子：
5.3
通讯作者：
Beal, M. Flint
中科院分区：
文献类型：
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作者：
Lorenzl, Stefan;Narr, Sabine;Beal, M. Flint
在肌萎缩侧索硬化症（ALS）中，死后脊髓组织中基质金属蛋白酶（MMPs）的表达增加，细胞外基质降解。采用酶谱法和原位酶谱法分析G93A转基因ALS小鼠脊髓组织中MMP-2和MMP-9的表达。G93A小鼠脊髓中MMP-9表达升高。为了分析MMPs的功能，我们研究了从30日龄（n = 19）开始口服NIMP抑制剂Ro 28-2653 （100 mg/kg）和从90日龄（n = 10）开始口服NIMP抑制剂Ro 28-2653对发病的影响。MM治疗？30日龄开始使用抑制剂Ro 28-2653可改善动物的运动性能，并显著延长动物的生存时间（136 +/- 12天对123 +/- 12天，平均+/- SD） （P < 0.05），但发病时给药对动物的生存时间没有显著改善。我们的实验表明，MMPs在ALS动物模型中表达，并可能在复杂的病理生理变化中发挥作用。合成MMP抑制剂的早期药理抑制延长了动物的生存期，这表明MMPs在疾病的早期阶段发挥了作用。(c) 2006爱思唯尔公司版权所有。
In amyotrophic lateral sclerosis (ALS), there is increased expression of matrix metalloproteinases (MMPs) and degradation of the extracellular matrix in postmortem spinal cord tissue. We used zymography and in situ zymography to analyze the expression of MMP-2 and MMP-9 in spinal cord tissue from the G93A transgenic mouse model of ALS. Expression of MMP-9 was increased in the spinal cord of G93A mice. For functional analysis of the role of MMPs, we investigated the effects of oral administration of the NIMP inhibitor Ro 28-2653 (100 mg/kg), starting at the age of 30 days (n = 19) and on disease onset (starting at the age of 90 days (n = 10)). Treatment with the MM? inhibitor Ro 28-2653 starting at 30 days of age improved motor performance and significantly (P < 0.05) prolonged the survival time of the animals (136 +/- 12 versus 123 +/- 12 days, mean +/- SD), however, administration at disease onset did not significantly improve survival time. Our experiments show that MMPs are expressed in an animal model of ALS and may play a role in the complex pathophysiologic changes. Early pharmacologic inhibition with a synthetic MMP inhibitor extends survival of the animals which suggest a role of MMPs in the early phase of the disease. (c) 2006 Elsevier Inc. All rights reserved.