The use of transgenic mouse models of amyotrophic lateral sclerosis in preclinical drug studies
The use of transgenic mouse models of amyotrophic lateral sclerosis in preclinical drug studies
复制标题
DOI：
10.1016/s0022-510x(97)00247-5
复制
发表时间：
1997-10-01
影响因子：
4.4
通讯作者：
Gurney, ME
中科院分区：
文献类型：
--
作者：
Gurney, ME
家族性肌萎缩侧索硬化症（ALS）患者中编码Cu，Zn超氧化物歧化酶（Cu，ZnSOD）的SOD 1基因突变的发现，使ALS病因学模型的建立成为可能。突变的SOD 1基因在转基因小鼠中的表达导致进行性麻痹疾病，其一般特征类似于人类的ALS。我们已经使用转基因模型来探索病因机制和筛选潜在的治疗方法。我们的研究结果和其他人的研究结果表明，家族性ALS突变导致铜，锌SOD的功能获得，增强了破坏性氧自由基的产生。这可能使运动神经元对周围谷氨酸的兴奋性毒性作用敏感，因为推定的谷氨酸能抑制剂如利鲁唑在转基因模型和人ALS中均具有治疗功效。这一发现强调了SOD 1-G93 A转基因小鼠模型在ALS临床前药物研究中的实用性。(C)1997年Elsevier Science B.V.
The discovery of mutations in the human SOD1 gene encoding Cu,Zn superoxide dismutase (Cu,Zn SOD) in patients with familial amyotrophic lateral sclerosis (ALS) has made possible the development of etiological models of the disease. Expression of mutant SOD1 genes in transgenic mice causes a progressive paralytic disease whose general features resemble ALS in humans. We have used the transgenic model to explore etiological mechanisms and to screen potential therapeutics. Our results and those of others show that familial ALS mutations cause a gain-of-function in Cu,Zn SOD that enhances the generation of damaging oxygen radicals. This may render motor neurons sensitive to the excitotoxic effects of ambient glutamate, as a putative glutamatergic inhibitor such as riluzole has therapeutic efficacy both in the transgenic model and in human ALS. This finding highlights the utility of the SOD1-G93A transgenic mouse model for preclinical drug studies in ALS. (C) 1997 Elsevier Science B.V.