Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1 G93A-induced motor neuron death
Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1 G93A-induced motor neuron death
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DOI：
10.1016/j.nbd.2006.12.023
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发表时间：
2007-05-01
影响因子：
6.1
通讯作者：
Robberecht, Wim
中科院分区：
文献类型：
--
作者：
Dewil, Maarten;dela Cruz, Vidal F.;Robberecht, Wim
肌萎缩性侧索硬化症（ALS）是一种以运动神经元选择性丧失为特征的神经退行性疾病。应激活化蛋白激酶（SAPK）已被认为在ALS的发病机制中发挥作用。我们研究了p38 MAPK与SOD1突变小鼠运动神经元变性的相关性。脊髓腹侧运动神经元和小胶质细胞中磷酸化-p38 MAPK水平升高。p38 mapk抑制剂SB203580完全抑制sod1突变体诱导的运动神经元凋亡，阻断lps诱导的小胶质细胞活化。Semapimod是一种适合临床使用的p38 MAPK抑制剂，它在一定程度上延长了突变SOD1小鼠的生存时间，但在很大程度上保护了运动神经元和近端轴突免受突变SOD1诱导的变性。我们的数据证实了突变SOD1小鼠中p38 MAPK的异常激活以及p38 MAPK参与突变SOD1诱导的运动神经元死亡。我们证明了p38 MAPK抑制对突变SOD1小鼠存活的影响，并揭示了对运动神经元存活的影响与对动物存活的影响之间的分离，后者可能取决于整个运动轴突的完整性。(c) 2007爱思唯尔公司版权所有。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective loss of motor neurons. Stress activated protein kinases (SAPK) have been suggested to play a role in the pathogenesis of ALS. We studied the relevance of p38 MAPK for motor neuron degeneration in the mutant SOD1 mouse. Increased levels of phospho-p38 MAPK were present in the motor neurons and microglia of the ventral spinal cord. The p38 MAPK-inhibitor, SB203580, completely inhibited mutant SOD1-induced apoptosis of motor neurons and blocked LPS-induced activation of microglia. Semapimod, a p38 MAPK inhibitor suitable for clinical use, prolonged survival of mutant SOD1 mice to a limited extent, but largely protected motor neurons and proximal axons from mutant SOD1-induced degeneration. Our data confirm the abnormal activation of p38 MAPK in mutant SOD1 mice and the involvement of p38 MAPK in mutant SOD1-induced motor neuron death. We demonstrate the effect of p38 MAPK inhibition on survival of mutant SOD1 mice and reveal a dissociation between the effect on survival of motor neurons and that on survival of the animal, the latter likely depending on the integrity of the entire motor axon. (c) 2007 Elsevier Inc. All rights reserved.