Wolfson Neuroscience Laboratories, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, London, United Kingdom.
PLoS One. 2011;6(9):e24189. doi: 10.1371/journal.pone.0024189. Epub 2011 Sep 1.
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurological disorder characterized by selective degeneration of upper and lower motor neurons. The primary triggers for motor neuron degeneration are unknown but inflammation, oxidative stress and mitochondrial defects have been identified as potential contributing factors. Metformin is an anti-type II diabetes drug that has anti-inflammatory and anti-oxidant properties, can bring about mitochondrial biogenesis and has been shown to attenuate pathology in mouse models of Huntington's disease and multiple sclerosis. We therefore hypothesized that it might increase survival in the SOD1(G93A) murine model of ALS.
METHODOLOGY/PRINCIPAL FINDINGS: Treatment of male and female SOD1(G93A) mice (n = ≥6 per sex) with 2 mg/ml metformin in the drinking water from 35 days, resulted in a significant increase in motor unit survival, as measured by in vivo electrophysiology at 100 days, in male EDL muscles (24+/-2 vs. 14+/-2 motor units, p<0.005) and female TA muscles (21+/-1 vs. 15+/-2 motor units, P = 0.0134). We therefore continued to test the effect of 0.5, 2 and 5 mg/ml metformin in the drinking water from 35 days on disease onset and progression (identified by twice weekly determination of weight and neurological score) as well as survival in male and female SOD1(G93A) mice (n = ≥14 per sex). Results for all groups were compared using Kaplan-Meier time to event analyses. In this survival study, metformin was unable to reduce pathology at any dose and had an unexpected dose-dependent negative effect on the onset of neurological symptoms (P = 0.0236) and on disease progression (P = 0.0362) in female mice.
CONCLUSIONS/SIGNIFICANCE: This study suggests that metformin is a poor candidate for clinical trial in ALS patients and that the possibility of harmful effects of metformin in female ALS patients with type II diabetes should be investigated.
肌萎缩侧索硬化症（ALS）是一种毁灭性的神经退行性疾病，其特征是上下运动神经元选择性退化。运动神经元退化的主要触发因素尚不清楚，但炎症、氧化应激和线粒体缺陷已被确定为潜在的促成因素。二甲双胍是一种抗 2 型糖尿病药物，具有抗炎和抗氧化特性，可以引起线粒体生物发生，并已被证明可以减轻亨廷顿病和多发性硬化症的小鼠模型中的病理学。因此，我们假设它可能会增加 SOD1(G93A)肌萎缩侧索硬化症小鼠模型的存活率。
方法/主要发现：从 35 天开始，雄性和雌性 SOD1(G93A)小鼠（每性别≥6 只）通过饮用水中的 2 mg/ml 二甲双胍治疗，通过 100 天的体内电生理学测量，可显著增加运动单位的存活，在雄性 EDL 肌肉中（24+/-2 与 14+/-2 运动单位，p<0.005）和雌性 TA 肌肉中（21+/-1 与 15+/-2 运动单位，P = 0.0134）。因此，我们继续测试从 35 天开始在饮用水中使用 0.5、2 和 5 mg/ml 二甲双胍对疾病发作和进展（通过每周两次确定体重和神经评分来确定）以及雄性和雌性 SOD1(G93A)小鼠的存活率的影响（每性别≥14 只）。使用 Kaplan-Meier 时间到事件分析比较所有组的结果。在这项生存研究中，二甲双胍不能降低任何剂量的病理学，并且对雌性小鼠的神经症状发作（P = 0.0236）和疾病进展（P = 0.0362）有出乎意料的剂量依赖性负面影响。
结论/意义：这项研究表明，二甲双胍不太可能成为 ALS 患者的临床试验候选药物，并且应该研究二甲双胍在患有 2 型糖尿病的女性 ALS 患者中的潜在有害作用。
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