Ouabain exacerbates botulinum neurotoxin-induced muscle paralysis via progression of muscle atrophy in mice
Ouabain exacerbates botulinum neurotoxin-induced muscle paralysis via progression of muscle atrophy in mice
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DOI：
10.2131/jts.35.795
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发表时间：
2010-12-01
影响因子：
2
通讯作者：
Ishir, Toshiaki
中科院分区：
文献类型：
--
作者：
Fujikawa, Ryu;Muroi, Yoshikage;Ishir, Toshiaki
A型肉毒神经毒素（BoNT/A）抑制离体肌肉神经肌肉接头处乙酰胆碱的释放，哇巴因可部分阻断其作用。然而，目前尚不清楚哇巴因是否减弱体内BoNT/A诱导的神经肌肉麻痹。在这项工作中，我们研究了哇巴因对BoNT/A诱导的小鼠神经肌肉麻痹的影响。在单次将BoNT/A注射到骨骼肌中后立即向小鼠腹腔内施用哇巴因。哇巴因对BoNT/A诱导的肌肉麻痹的影响通过手指外展评分（DAS）测定定量监测肌肉张力和手指外展来评估。哇巴因单次给药显著延长了BoNT/A诱导的神经肌肉麻痹。此外，连续每天注射哇巴因加剧了BoNT/A诱导的神经肌肉麻痹，并导致在分离的BoNT/A注射肌肉中测定的抽搐和强直力量显著降低。接下来，我们研究了哇巴因对BoNT/A诱导的肌肉萎缩的影响。哇巴因的管理导致的肌原纤维横截面积（CSA）的减少14后BoNT/A注射。此外，重复施用哇巴因增加了BoNT/A注射肌肉中作为肌肉萎缩标志物的泛素连接酶的mRNA表达水平。这些结果表明，哇巴因通过BoNT/A诱导的肌肉萎缩的显著进展而加剧BoNT/A诱导的神经肌肉麻痹。
Botulinum neurotoxin serotype A (BoNT/A) inhibits acetylcholine release at the neuromuscular junction in isolated muscles, and ouabain can partially block its effect. However, it is not clear whether ouabain attenuates BoNT/A-induced neuromuscular paralysis in vivo. In this work, we investigated the effects of ouabain on BoNT/A-induced neuromuscular paralysis in mice. Ouabain was administered to mice intraperitoneally immediately after a single injection of BoNT/A into skeletal muscle. The effects of ouabain on BoNT/A-induced muscle paralysis were assessed by quantitative monitoring of muscle tension and digit abduction via the digit abduction scoring (DAS) assay. A single administration of ouabain significantly prolonged BoNT/A-induced neuromuscular paralysis. Moreover, consecutive daily injection of ouabain exacerbated BoNT/A-induced neuromuscular paralysis, and led to a significant decrease in both twitch and tetanic forces as assayed in isolated BoNT/A-injected muscles. We next looked at the effects of ouabain on BoNT/A-induced muscle atrophy. Administration of ouabain led to a decrease in the myofibrillar cross-sectional area (CSAs) by 14 post-BoNT/A injection. In addition, repeated administration of ouabain increased mRNA expression levels of ubiquitin ligases, which are markers of muscle atrophy, in BoNT/A-injected muscle. These results suggest that ouabain exacerbates BoNT/A-induced neuromuscular paralysis via a marked progression of BoNT/A-induced muscle atrophy.