A therapeutic role for cyclooxygenase-2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis
A therapeutic role for cyclooxygenase-2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis
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DOI：
10.1096/fj.02-0876fje
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发表时间：
2003-02-01
期刊：
影响因子：
4.8
通讯作者：
Pasinetti, GM
中科院分区：
文献类型：
--
作者：
Pompl, PN;Ho, L;Pasinetti, GM
最近的研究表明，促炎酶环氧合酶（考克斯）-2，一种参与炎症级联反应，但也正常的神经元活动的酶，在肌萎缩侧索硬化症（ALS）患者和ALS小鼠模型系统的脑和脊髓中升高。在此证据的基础上，我们探讨了考克斯-2抑制对ALS样疾病的发生和进展的影响，在G93 A人超氧化物歧化酶（SOD）1 ALS小鼠模型。我们发现，在饲料中预防性给予尼美舒利（一种优选的考克斯-2抑制剂）可显著延迟ALS型运动障碍的发作。相对于未处理的SOD 1-G93 A对照，这种ALS代谢的延迟与SOD 1-G93 A转基因小鼠脊髓中前列腺素E-2升高的抑制在时间上重叠。本研究强烈支持考克斯-2在ALS病理生理学中的作用，并提供了第一个实验证据，即用考克斯-2抑制剂预防性治疗可以显著延迟ALS的SOD 1-G93 A转基因小鼠模型中运动功能障碍的发作。
Recent studies indicate that the proinflammatory enzyme cyclooxygenase (COX)-2, an enzyme involved in inflammatory cascades but also normal neuronal activities, is elevated in the brain and spinal cord of amyotrophic lateral sclerosis (ALS) patients and ALS mouse model systems. On the basis of this evidence, we explored the impact of COX-2 inhibition on the onset and progression of ALS-like disease in the G93A human superoxide dismutase (SOD)1 mouse model of ALS. We found that prophylactic administration of nimesulide, a preferential COX-2 inhibitor, in the feed resulted in a significant delay in the onset of ALS type motor impairment. This delay of ALS symptomatology temporally overlapped with the inhibition of prostaglandin E-2 elevation in the spinal cord of SOD1-G93A transgenic mice relative to untreated SOD1-G93A controls. This study strongly supports a role for COX-2 in the pathophysiology of ALS and provides the first experimental evidence that prophylactic treatment with COX-2 inhibitors can significantly delay the onset of motor dysfunction in the SOD1-G93A transgenic mouse model of ALS.