DOXORUBICIN-INDUCED MOTOR NEURON AND SCHWANN CELL DEATH

阿霉素(阿霉素)是一种自体荧光的蒽环类药物 作用于细胞核的抗肿瘤抗生素，通过 在DNA碱基对之间插入从而抑制DNA- 定向信使RNA合成。神经内微量注射阿司匹林 0.19-0.38杯阿霉素导致迟发性选择性雪旺 无髓鞘细胞变性和伴随脱髓鞘 显著影响轴突。但是，当大于或 相当于注射0.5杯阿霉素，也是退行性的 转移到前角细胞导致延迟性进展 这些下层运动神经元的退化。 我们计划在实验中研究这两个可分离的过程 更多细节。同时使用电生理和 神经病理学方法我们计划进一步研究阿霉素- 诱导运动神经元变性模型的建立 肌萎缩侧索硬化症(ALS)。我们将确定这样的情况是否 轴突长度、轴突直径和神经元的特征 功能与神经元易损性有关。使用免疫- 我们计划用组织化学方法来鉴定卫星细胞 它们在阿霉素细胞间转移后被标记 来自前角细胞。此外，还可能存在跨细胞的 这种毒素向中间神经元和上运动神经元的转运 突出到前角的。这种新的动物模型是一种 毒素诱导的运动性退行性变可能为 人类运动神经元变性的病因学，尤其是 肌萎缩侧索硬化。此外，细胞间神经毒性可能是一种 其他神经系统发病机制的重要线索 疾病。 在另一组观察中，我们计划进一步描述一些 阿霉素诱导的病理生理后果 周围神经雪旺细胞变性/脱髓鞘。 使用针对Na+组成部分产生的抗体 通道，我们将确定Na+通道沿 脱髓鞘和再生髓鞘轴突。将这些关联起来 免疫细胞化学结果与电生理数据 应提供有关下列机制的信息 脱髓鞘轴突重新建立传导。这些研究是 对了解其病理生理的重要性显而易见 人类脱髓鞘疾病中发生的变化。

Doxorubicin (Adriamycin) is an autofluorescent anthracycline antineoplastic antibiotic that acts at the cell nucleus by intercalating between base pairs of DNA thus inhibiting DNA- directed messenger RNA synthesis. Intraneural microinjection of 0.19-0.38 mug of doxorubicin causes a delayed selective Schwann cell degeneration and accompanying demyelination without significantly affecting axons. However when greater than or equal to 0.5 mug of doxorubicin is injected, it is also retrogradely transported to anterior horn cells causing a delayed progressive degeneration of these lower motor neurons. We plan to study these two experimentally separable processes in greater detail. Using both electrophysiological and neuropathological methods we plan to further study doxorubicin- induced motor neuron degeneration as as possible model of amyotrophic lateral sclerosis (ALS). We will determine if such characteristics as axonal length, axonal diameter, and neuronal function correlate with neuron vulnerability. Using immuno- histochemical methods we plan to identify the satellite cells which are labeled following intercellular transfer of doxorubicin from anterior horn cells. In addition, there may be transcellular transport of this toxin to interneurons and upper motor neurons projecting to the anterior horn. This new animal model of a toxin-induced motor degeneration may provide new insights into the etiology of human motor neuron degenerations, especially ALS. additionally the intercellular of neurotoxicity could be an important clue to the pathogenesis of other nervous system diseases. In a separate set of observations we plan to further describe some of the pathophysiological consequences of doxorubicin-induced Schwann cell degeneration/demyelination in peripheral nerve. Using antibodies generated against component parts of the Na+ channel, we will determine the Na+ channel distribution along demyelinated and remyelinating axons. Correlating these immunocytochemical findings with electrophysiological data should provide information concerning the mechanism by which demyelinated axons re-establish conduction. These studies are of obvious importance for understanding the pathophysiological changes that occur in human demyelinating diseases.