Integrative role of cPLA2 with COX-2 and the effect of non-steriodal anti-inflammatory drugs in a transgenic mouse model of amyotrophic lateral sclerosis
Integrative role of cPLA2 with COX-2 and the effect of non-steriodal anti-inflammatory drugs in a transgenic mouse model of amyotrophic lateral sclerosis
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DOI：
10.1111/j.1471-4159.2005.03024.x
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发表时间：
2005-04-01
影响因子：
4.7
通讯作者：
Beal, MF
中科院分区：
文献类型：
--
作者：
Kiaei, M;Kipiani, K;Beal, MF
环氧化酶-2（考克斯-2）是肌萎缩侧索硬化症（ALS）炎症通路中的关键分子。胞浆磷脂酶A（cPLA 2）是环加氧酶的重要底物。因此，我们研究了cPLA 2在人ALS和突变型Cu/Zn超氧化物歧化酶（SOD 1）转基因小鼠中的表达及其与考克斯-2的关系。免疫组织化学和实时荧光定量RT-PCR显示突变SOD 1小鼠腰髓cPLA 2蛋白及其mRNA水平升高。与对照组相比，家族性ALS（FALS）和散发性ALS（SALS）的腰脊髓切片中的考克斯-2免疫反应性增加，并且FALS患者的cPLA 2免疫反应性增加。与同窝对照组相比，口服非选择性环氧合酶（考克斯）抑制剂舒林酸延长了G93 A SOD 1小鼠的生存期（10%）。舒林酸，以及选择性考克斯-2抑制剂，罗非昔布和塞来昔布降低了G93 A转基因小鼠腰脊髓中的cPLA 2免疫反应性。舒林酸治疗保留了G93 A SOD 1转基因小鼠脊髓中的运动神经元，并减少了小胶质细胞活化和星形胶质细胞增多。这些结果表明，cPLA 2在向与SOD 1突变相关的ALS中的考克斯-2驱动的炎症通路提供花生四烯酸中起重要作用。
Cyclooxygenase-2 (COX-2) is a key molecule in the inflammatory pathway in amyotrophic lateral sclerosis (ALS). Cytosolic phospholipase A (cPLA2) is an important enzyme providing substrate for cyclooxygenases. We therefore examined cPLA2 expression in human ALS and mutant Cu/Zn superoxide dismutase (SOD1) transgenic mice and its relation to COX-2. Immunohistochemistry and real-time RT-PCR revealed elevated cPLA2 protein and its mRNA levels in the lumbar spinal cord of mutant SOD1 mice. COX-2 immunoreactivity was increased in lumbar spinal cord sections from both familial ALS (FALS) and sporadic ALS (SALS) as compared to controls, and cPLA2 immunoreactivity was increased in a patient with FALS. Oral administration of the non-selective cyclooxygenase (COX) inhibitor, sulindac, extended the survival (by 10%) of G93A SOD1 mice as compared to littermate controls. Sulindac, as well as the selective COX-2 inhibitors, rofecoxib and celecoxib reduced cPLA2 immunoreactivity in the lumbar spinal cord of G93A transgenic mice. Sulindac treatment preserved motor neurons, and reduced microglial activation and astrocytosis, in the spinal cord of G93A SOD1 transgenic mice. These results suggest that cPLA2 plays an important role in supplying arachidonic acid to the COX-2 driven inflammatory pathway in ALS associated with SOD1 mutations.