PDF(Pubmed)
Abstract：
Amyotrophic lateral sclerosis (ALS) is an extremely complex neurodegenerative disease involving different cell types, but motoneuronal loss represents its main pathological feature. Moreover, compensatory plastic changes taking place in parallel to neurodegeneration are likely to affect the timing of ALS onset and progression and, interestingly, they might represent a promising target for disease-modifying treatments. Therefore, a simplified animal model mimicking motoneuronal loss without the other pathological aspects of ALS has been established by means of intramuscular injection of cholera toxin-B saporin (CTB-Sap), which is a targeted neurotoxin able to kill motoneurons by retrograde suicide transport. Previous studies employing the mouse CTB-Sap model have proven that spontaneous motor recovery is possible after a subtotal removal of a spinal motoneuronal pool. Although these kinds of plastic changes are not enough to counteract the functional effects of the progressive motoneuron degeneration, it would nevertheless represent a promising target for treatments aiming to postpone ALS onset and/or delay disease progression. Herein, the mouse CTB-Sap model has been used to test the efficacy of mitochondrial division inhibitor 1 (Mdivi-1) as a tool to counteract the CTB-Sap toxicity and/or to promote neuroplasticity. The homeostasis of mitochondrial fission/fusion dynamics is indeed important for cell integrity, and it could be affected during neurodegeneration. Lesioned mice were treated with Mdivi-1 and then examined by a series of behavioral test and histological analyses. The results have shown that the drug may be capable of reducing functional deficits after the lesion and promoting synaptic plasticity and neuroprotection, thus representing a putative translational approach for motoneuron disorders.
摘要：
肌萎缩侧索硬化症（ALS）是一种极其复杂的神经退行性疾病，涉及不同的细胞类型。但运动神经元丢失是其主要病理特征。此外，代偿性塑料变化发生在平行的神经变性可能会影响的时间ALS的发病和进展，有趣的是,它们可能是改善疾病治疗的有希望的目标。因此,通过肌肉注射霍乱毒素B皂草素（CTB-Sap），建立了模拟运动神经元丢失而没有ALS其他病理方面的简化动物模型，这是一种有针对性的神经毒素，能够通过逆行自杀运输杀死运动神经元。先前使用小鼠CTB-Sap模型的研究已经证明，在脊髓运动神经元池次全切除后，自发运动恢复是可能的。尽管这些可塑性变化不足以抵消进行性运动神经元变性的功能影响，尽管如此,它仍将代表旨在推迟ALS发作和/或延迟疾病进展的治疗的有希望的目标.在这里，小鼠CTB-Sap模型已用于测试线粒体分裂抑制剂1(Mdivi-1)作为抵消CTB-Sap毒性和/或促进神经可塑性的工具的功效.线粒体裂变/融合动力学的稳态对于细胞完整性确实很重要，它可能会在神经变性过程中受到影响。用Mdivi-1处理病变小鼠,然后通过一系列行为测试和组织学分析进行检查。结果表明，该药物可能能够减少损伤后的功能缺陷，促进突触可塑性和神经保护，因此代表了运动神经元疾病的推定翻译方法。
