Table_1_Assessing the therapeutic impact of resveratrol in ALS SOD1-G93A mice with electrical impedance myography.XLSX

To aid in the identification of new treatments for amyotrophic lateral sclerosis (ALS), convenient biomarkers are needed to effectively and uniformly measure drug efficacy. To this end, we assessed the effects of the nutraceutical resveratrol (RSV) on disease onset and overall survival in SOD1-G93A (ALS) mice and compared several standard biomarkers including body mass, motor score (MS), paw grip endurance (PGE), and compound motor action potential (CMAP) amplitude, with the technique of electrical impedance myography (EIM) to follow disease progression. Eighteen ALS mice (nine females, nine males) received RSV in the chow (dose: 120 mg/kg/day) starting at 8 weeks of age; 19 ALS mice (nine females, 10 males) received normal chow; 10 wild type (WT) littermates (five females, five males) fed standard chow served as controls. Biomarker assessments were performed weekly beginning at 8 weeks. No differences in either disease onset or overall survival were found between RSV-treated and untreated ALS mice of either sex; moreover, all biomarkers failed to identify any beneficial effect of RSV when administered at this dose. Therefore, for the comparative evaluation of the ability of the various biomarkers to detect the earliest symptoms of disease, data from all animals (i.e., RSV-treated and untreated ALS mice of both sexes) were combined. Of the biomarkers tested, EIM impedance values, i.e., surface EIM longitudinal phase at 50 kHz (LP 50 kHz), and CMAP amplitude showed the earliest significant changes from baseline. LP 50 kHz values showed a rate of decline equivalent to that of CMAP amplitude and correlated with both PGE and CMAP amplitude [Spearman rho = 0.806 (p = 0.004) and 0.627 (p = 0.044), respectively]. Consistent with previous work, these findings indicate that surface EIM can serve as an effective non-invasive biomarker for preclinical drug testing in rodent models of ALS.

为助力肌萎缩侧索硬化症（amyotrophic lateral sclerosis, ALS）新型治疗手段的研发，亟需便捷可靠的生物标志物以实现药物疗效的高效、统一评估。为此，我们评估了营养补充剂白藜芦醇（resveratrol, RSV）对SOD1-G93A型肌萎缩侧索硬化症小鼠的疾病发病时间与总生存期的影响，并对比了包括体重、运动评分（motor score, MS）、握力耐力（paw grip endurance, PGE）、复合肌肉动作电位（compound motor action potential, CMAP）波幅在内的多种标准生物标志物，同时采用电阻抗肌电图（electrical impedance myography, EIM）技术监测疾病进展。本研究共纳入37只ALS小鼠（9雌9雄），自8周龄起给予含120 mg/kg/天白藜芦醇的饲料；另有19只ALS小鼠（9雌10雄）给予正常饲料作为对照组；同时纳入10只野生型（wild type, WT）同窝小鼠（5雌5雄），给予标准饲料作为空白对照。自8周龄起，每周进行一次生物标志物检测。研究发现，无论雌雄，白藜芦醇给药组与未给药组ALS小鼠的疾病发病时间及总生存期均无显著差异；且在该给药剂量下，所有检测的生物标志物均未体现白藜芦醇的任何获益效果。因此，为对比评估各类生物标志物检测疾病早期症状的能力，我们将所有动物（即雌雄白藜芦醇给药组与未给药组ALS小鼠）的实验数据进行合并分析。在所检测的生物标志物中，EIM阻抗值（即50 kHz时的表面EIM纵向相位，LP 50 kHz）与CMAP波幅最早出现相对于基线的显著变化。LP 50 kHz的下降速率与CMAP波幅相当，且与PGE及CMAP波幅均呈显著相关（斯皮尔曼秩相关系数Spearman rho分别为0.806，p=0.004；0.627，p=0.044）。与既往研究结果一致，本研究结果表明，表面EIM可作为ALS啮齿类动物模型临床前药物测试的有效非侵入性生物标志物。