Reinholz M M, Merkle C M, Poduslo J F
Department of Neurology and, Mayo Clinic and Foundation, Rochester, Minnesota, 55905, USA.
Exp Neurol. 1999 Sep;159(1):204-16. doi: 10.1006/exnr.1999.7142.
Dominant mutations in the copper/zinc superoxide dismutase (SOD1) gene have been observed in 15-20% of familial amyotrophic lateral sclerosis (FALS) cases. The mechanism by which SOD1 mutations result in motor neuron degeneration in FALS mice partly involves oxidative damage and an increased peroxidase activity of the mutant SOD1. A new therapeutic approach designed to eliminate the substrate of this peroxidase activity was examined in two lines of transgenic mice expressing the FALS-linked mutation glycine to alanine (G93A). We investigated the ability of putrescine-modified catalase (PUT-CAT), an antioxidant enzyme that removes hydrogen peroxide and has increased permeability at the blood-brain barrier, to modify the time course of the SOD1 mutation-induced motor neuron disease in these FALS mice. Continuous, subcutaneous administration of PUT-CAT significantly delayed the age at which onset of clinical disease occurred (indicated by loss of splay and/or tremors of hindlimbs) in a high-expressor line of FALS transgenic mice. Intraperitoneal injection of PUT-CAT given two times per week also significantly delayed the onset of clinical disease in a low-expressor line of FALS mice. PUT-CAT also significantly delayed the age at which clinical weakness developed (quantified by measuring the shortening of stride length) in both lines of FALS animals. No significant changes were observed in the survival times of the high-expressor FALS mice in any of the treatment groups. However, a trend toward a prolongation of survival was observed in the PUT-CAT-treated low-expressor FALS mice. These results support the role of free radical-mediated damage in the cascade of events leading to motor neurodegeneration in FALS and indicate that PUT-CAT interacts with a critical step in this cascade to delay the onset of clinical disease as well as the development of clinical weakness in FALS transgenic mice.
在15%-20%的家族性肌萎缩侧索硬化症（FALS）病例中观察到铜/锌超氧化物歧化酶（SOD1）基因的显性突变。SOD1突变导致FALS小鼠运动神经元变性的机制部分涉及氧化损伤和突变型SOD1过氧化物酶活性的增加。在两个表达与FALS相关的甘氨酸到丙氨酸（G93A）突变的转基因小鼠品系中，研究了一种旨在消除这种过氧化物酶活性底物的新治疗方法。我们研究了腐胺修饰的过氧化氢酶（PUT-CAT），一种能清除过氧化氢且在血脑屏障处通透性增加的抗氧化酶，对这些FALS小鼠中SOD1突变诱导的运动神经元疾病病程的影响。在一个高表达的FALS转基因小鼠品系中，持续皮下注射PUT-CAT显著延迟了临床疾病发作的年龄（以后肢展开和/或震颤消失为指标）。每周两次腹腔注射PUT-CAT也显著延迟了低表达FALS小鼠品系临床疾病的发作。PUT-CAT还显著延迟了两个FALS动物品系中临床肌无力出现的年龄（通过测量步长缩短来量化）。在任何治疗组中，高表达FALS小鼠的存活时间均未观察到显著变化。然而，在接受PUT-CAT治疗的低表达FALS小鼠中观察到存活时间有延长的趋势。这些结果支持了自由基介导的损伤在导致FALS运动神经元变性的一系列事件中的作用，并表明PUT-CAT与这一系列事件中的关键步骤相互作用，以延迟FALS转基因小鼠临床疾病的发作以及临床肌无力的发展。
