延缓G1H-G93A转基因小鼠肌萎缩性侧索硬化症进展的新策略:口服不是嘌呤回收途径底物的黄嘌呤氧化还原酶抑制剂

S. Kato, Masako Kato, Teruo Kusano, T. Nishino
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引用次数: 13

摘要

肌萎缩性侧索硬化症(ALS), Lou Gehrig 's病,是一种累及上、下运动神经元的进行性致死性神经退行性疾病。从80日龄开始,我们给携带人类突变体G93A超氧化物歧化酶1基因拷贝数为25的G1H-G93A小鼠口服4种黄嘌呤氧化还原酶(XOR)抑制剂。三种非嘌呤类似物抑制剂(TEI-6720:非布司他,Y-700和FYX-051),但不含嘌呤类似物环(吡唑啉嘧啶环)的别嘌呤醇,显著延迟疾病发作,延长生存期和疾病分期持续时间,改善临床症状,减轻体重减轻。运动测试(伸展反射、斜面、足迹、旋转杆和平衡木测试)显示,这3种抑制剂显著改善了G1H-G93A小鼠的运动功能。即使在早期症状出现后给予TEI-6720或Y-700,也能看到疾病的显著改善。晚期的组织病理学评估显示,与安慰剂或别嘌呤醇治疗的小鼠相比,TEI-6720治疗的G1H-G93A小鼠的运动神经元保存良好,包涵体较少。我们的研究结果表明,这3种非嘌呤类似物XOR抑制剂可能通过嘌呤回收途径增加高能化合物的供应,从而保护运动神经元免受死亡。这一策略可能适用于ALS患者的口服治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
New Strategy That Delays Progression of Amyotrophic Lateral Sclerosis in G1H-G93A Transgenic Mice: Oral Administration of Xanthine Oxidoreductase Inhibitors That Are Not Substrates for the Purine Salvage Pathway
Amyotrophic lateral sclerosis (ALS), Lou Gehrig’s disease, is a progressive fatal neurodegenerative disease that involves both upper and lower motor neurons. We orally administered 4 xanthine oxidoreductase (XOR) inhibitors to G1H-G93A mice carrying 25 transgene copy numbers of human mutant G93A superoxide dismutase 1, from 80 days of age. Three nonpurine-analogue inhibitors (TEI-6720: Febuxostat, Y-700 and FYX-051), but not allopurinol with a purine analogue ring (pyrazolo pyrimidine ring), significantly delayed disease onset, prolonged survival and the duration of disease stages, improved clinical signs, and alleviated weight loss. Exercise testing (extension reflex, inclined plane, footprint, rotarod, and beam balance tests) showed significantly improved motor function in the G1H-G93A mice treated with these 3 inhibitors. Significant amelioration of disease was seen even when TEI-6720 or Y-700 was administered after the appearance of early signs. Histopathological evaluation in the late stage revealed that G1H-G93A mice treated with TEI-6720 had well-preserved motor neurons and fewer inclusion bodies, compared with mice treated with placebo or with allopurinol. Our results indicate that these 3 nonpurine-analogue XOR inhibitors might increase the supply of high-energy compounds via the purine salvage pathway, thereby protecting motor neurons against death. This strategy may be applicable for oral therapy of ALS patients.
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