Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse.
Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse.
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DOI：
10.1371/journal.pone.0140316
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Iwasaki Y
中科院分区：
文献类型：
--
作者：
Ikeda K;Iwasaki Y
依达拉奉是一种自由基清除剂，广泛用于日本急性脑梗死患者。这种抗氧化剂可能对其他神经系统疾病具有治疗潜力。肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，影响上下运动神经元，导致发病后3-5年内死亡。依达拉奉的III期临床试验表明，对ALS患者没有显着影响。然而，最近的第2项双盲试验已证实依达拉奉在经修订的埃尔埃斯科里亚ALS诊断标准确诊的患者中具有治疗获益。先前的两项研究表明，依达拉奉减轻了突变型超氧化物歧化酶1转基因小鼠或大鼠（家族性ALS动物模型）的运动症状或运动神经元变性。在此，我们研究了这种自由基清除剂是否可以延缓摇摆小鼠，散发性ALS样模型的运动功能障碍和神经病理学变化的进展。在出生后3-4周龄诊断出疾病发作后，wobbler小鼠通过腹膜内给药每天接受依达拉奉（1或10 mg/kg，n = 10/组）或溶媒（n = 10），持续4周。比较三组患者的运动症状和神经病理改变。与溶剂相比，较高剂量（10 mg/kg）的依达拉奉治疗显著减轻了前肢的肌无力和挛缩，并抑制了二头肌的去神经萎缩和颈部运动神经元的变性。先前和当前的研究表明依达拉奉在三种啮齿动物ALS样模型中具有神经保护作用。这种药物似乎值得在美国和欧洲以及日本的ALS患者中进行临床试验。
Edaravone, a free radical scavenger is used widely in Japanese patients with acute cerebral infarction. This antioxidant could have therapeutic potentials for other neurological diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the upper and the lower motor neuron, leading to death within 3–5 years after onset. A phase III clinical trial of edaravone suggested no significant effects in ALS patients. However, recent 2nd double-blind trial has demonstrated therapeutic benefits of edaravone in definite patients diagnosed by revised El Escorial diagnostic criteria of ALS. Two previous studies showed that edaravone attenuated motor symptoms or motor neuron degeneration in mutant superoxide dismutase 1-transgenic mice or rats, animal models of familial ALS. Herein we examined whether this radical scavenger can retard progression of motor dysfunction and neuropathological changes in wobbler mice, sporadic ALS-like model. After diagnosis of the disease onset at the postnatal age of 3–4 weeks, wobbler mice received edaravone (1 or 10 mg/kg, n = 10/group) or vehicle (n = 10), daily for 4 weeks by intraperitoneal administration. Motor symptoms and neuropathological changes were compared among three groups. Higher dose (10 mg/kg) of edaravone treatment significantly attenuated muscle weakness and contracture in the forelimbs, and suppressed denervation atrophy in the biceps muscle and degeneration in the cervical motor neurons compared to vehicle. Previous and the present studies indicated neuroprotective effects of edaravone in three rodent ALS-like models. This drug seems to be worth performing the clinical trial in ALS patients in the United States of American and Europe, in addition to Japan.