Fujisawa Takao, Takahashi Motoo, Tsukamoto Yuka, Yamaguchi Namiko, Nakoji Masayoshi, Endo Megumi, Kodaira Hiroshi, Hayashi Yuki, Nishitoh Hideki, Naguro Isao, Homma Kengo, Ichijo Hidenori
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Tokyo Research Park, R&D Division, Kyowa Hakko Kirin Co., Ltd., 3-6-6, Asahi-machi, Machida-shi, Tokyo 194-8533, Japan.
Hum Mol Genet. 2016 Jan 15;25(2):245-53. doi: 10.1093/hmg/ddv467. Epub 2015 Nov 24.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure. To develop effective treatments for this devastating disease, an appropriate strategy for targeting the molecule responsible for the pathogenesis of ALS is needed. We previously reported that mutant SOD1 protein causes motor neuron death through activation of ASK1, a mitogen-activated protein kinase kinase kinase. Additionally, we recently developed K811 and K812, which are selective inhibitors for ASK1. Here, we report the effect of K811 and K812 in a mouse model of ALS (SOD1(G93A) transgenic mice). Oral administration of K811 or K812 significantly extended the life span of SOD1(G93A) transgenic mice (1.06 and 1.08% improvement in survival). Moreover, ASK1 activation observed in the lumbar spinal cord of mice at the disease progression stage was markedly decreased in the K811- and K812-treated groups. In parallel, immunohistochemical analysis revealed that K811 and K812 treatment inhibited glial activation in the lumbar spinal cord of SOD1(G93A) transgenic mice. These results reinforce the importance of ASK1 as a therapeutic target for ALS treatment.
肌萎缩侧索硬化症（ALS）是一种无法治愈的致命性神经退行性疾病。为了开发针对这种毁灭性疾病的有效治疗方法，需要一种合适的策略来靶向负责ALS发病机制的分子。我们之前报道过，突变型超氧化物歧化酶1（SOD1）蛋白通过激活丝裂原活化蛋白激酶激酶激酶ASK1导致运动神经元死亡。此外，我们最近开发了K811和K812，它们是ASK1的选择性抑制剂。在此，我们报告K811和K812在ALS小鼠模型（SOD1(G93A)转基因小鼠）中的作用。口服K811或K812可显著延长SOD1(G93A)转基因小鼠的寿命（生存率提高1.06%和1.08%）。此外，在疾病进展阶段小鼠腰脊髓中观察到的ASK1激活在K811和K812治疗组中明显降低。同时，免疫组织化学分析显示，K811和K812治疗可抑制SOD1(G93A)转基因小鼠腰脊髓中的神经胶质细胞激活。这些结果强化了ASK1作为ALS治疗靶点的重要性。
