Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis
Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis
复制标题
利鲁唑对肌萎缩侧索硬化症转基因大鼠模型没有显示出治疗效果。
DOI：
10.2174/1567202617666200409125227
复制
发表时间：
2020-01-01
影响因子：
2.1
通讯作者：
Bi, Fangfang
中科院分区：
文献类型：
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作者：
Chen, Si;Liao, Qiao;Bi, Fangfang
背景
肌萎缩侧索硬化症（ALS）是一种神经系统疾病，临床上以运动系统功能障碍为特征，其中TAR DNA结合蛋白43（TDP-43）的神经元内积累是病理标志。阿曲唑是ALS患者的主要处方药，但其治疗效果似乎有限。TDP-43转基因小鼠是ALS机制/转化研究的现有动物模型。
方法
我们开发了一种表达突变型人TDP-43转基因（TDP-43 M337 V）的ALS转基因大鼠模型，并评估了阿曲唑对该模型的治疗效果。相对于对照组，具有由神经丝重亚基（NEF）基因促进的TDP-43 M337 V表达或特别是由胆碱乙酰转移酶（ChAT）基因促进的运动神经元中的表达的大鼠表现出活动性和握力的进行性恶化，沿着运动神经元的丧失、小胶质细胞的激活以及脊髓中TDP-43和遍在蛋白聚集的神经元内积聚。
结果
与溶剂对照相比，灌胃给予阿曲唑（30 mg/kg/d）并没有减轻转基因动物的行为缺陷，也没有改变转基因动物的神经病理学。
结论
这些发现表明，转基因大鼠概括了人类ALS的基本神经和神经病理学特征，而阿曲唑治疗不能阻止这种新的转基因啮齿动物ALS模型中行为和组织病理学表型的发展。
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a neurological disorder clinically characterized by motor system dysfunction, with intraneuronal accumulation of the TAR DNA-binding protein 43 (TDP-43) being a pathological hallmark. Riluzole is a primarily prescribed medicine for ALS patients, while its therapeutical efficacy appears limited. TDP-43 transgenic mice are existing animal models for mechanistic/translational research into ALS.
METHODS
We developed a transgenic rat model of ALS expressing a mutant human TDP-43 transgene (TDP-43M337V) and evaluated the therapeutic effect of Riluzole on this model. Relative to control, rats with TDP-43M337V expression promoted by the neurofilament heavy subunit (NEF) gene or specifically in motor neurons promoted by the choline acetyltransferase (ChAT) gene showed progressive worsening of mobility and grip strength, along with loss of motor neurons, microglial activation, and intraneuronal accumulation of TDP-43 and ubiquitin aggregations in spinal cord.
RESULTS
Compared to vehicle control, intragastric administration of Riluzole (30mg/kg/d) did not mitigate the behavioral deficits nor alter the neuropathologies in the transgenics.
CONCLUSION
These findings indicate that transgenic rats recapitulate the basic neurological and neuropathological characteristics of human ALS, while Riluzole treatment can not halt the development of the behavioral and histopathological phenotypes in this new transgenic rodent model of ALS.