ROLE OF CALCIUM IN ACRYLAMIDE NEUROTOXICITY

长期暴露于丙烯酰胺导致骨骼肌无力相关 远端轴突病变 造成这种情况的生化病变 尚未发现神经元损伤。 最近的研究表明， 多种损伤性神经元钙离子浓度升高 过程（如化学，疾病）是导致 神经元损伤和/或死亡。 因此，丙烯酰胺可能通过以下方式产生损伤： 导致细胞膜变得“渗漏”，从而允许 细胞外钙和其它离子。 随而增加 胞浆钙离子可通过抑制神经细胞凋亡而引起神经细胞损伤 线粒体呼吸，通过破坏细胞骨架结构或通过 轴突运输的直接抑制。 拟议的调查将 确定钙浓度的逐渐增加是否 时间上与丙烯酰胺中毒有关 这些研究将涉及 使用来自丙烯酰胺处理大鼠的神经组织和神经细胞 培养暴露在这种神经毒素下的系统 具体而言，初步研究 将采用原子吸收分光光度法测量 丙烯酰胺诱导的总钙浓度变化。 变化 钙水平将在时间上与 丙烯酰胺引起的神经元损伤 将使用放射自显影（45 Ca） 来识别丙烯酰胺处理的大鼠大脑中的细胞核或区域， 表现出钙摄取和/或保留的变化。 这些领域（如 小脑）可能代表了被选择性损伤的结构， 丙烯酰胺，因此，重要的是参与的表现， 神经毒性 钙离子亚细胞分布的改变， 丙烯酰胺产生的其他离子将使用x射线测定 微观分析 用这种技术可以测量离子 线粒体和其他亚细胞器中的浓度。 丙烯酰胺 神经毒性可能是由钙对神经细胞的抑制作用介导的。 线粒体呼吸 因此，氧摄取将使用 神经组织和神经细胞培养物中的克拉克氧电极 暴露在丙烯酰胺中 这项研究的长期目标是确定 钙在丙烯酰胺引起的远端轴突病中的作用， 其他神经毒素 这项研究的结果可能会暗示 钙参与人类疾病状态（例如婴儿神经轴突性 营养不良），其与类似于那些 由丙烯酰胺引起的。

Chronic exposure to acrylamide causes skeletal muscle weakness associated with a distal axonopathy. The biochemical lesion responsible for this neuronal damage has not been identified. Recent research indicates that an increase in intraneuronal calcium induced by a variety of injurious processes (e.g. chemical, disease) is responsible for the resulting neuronal damage and/or death. Thus, acrylamide might produce injury by causing cellular membranes to become "leaky" thereby allowing an influx of extracellular calcium and other ions. The resulting increase in cytoplasmic calcium could cause nerve cell injury by inhibiting mitochondrial respiration, by disrupting cytoskeletal structure or by a direct inhibition of axonal transport. The proposed investigation will determine whether a progressive increase in the concentration of calcium is temporally related to acrylamide intoxication. These studies will involve the use of nervous tissues from acrylamide-treated rats and nerve cell culture systems exposed to this neurotoxin. Specifically, initial studies will employ atomic absorption spectrophotometry to measure acrylamide-induced changes in total calcium concentrations. Changes in calcium levels will be correlated temporally with the development of neuronal damage caused by acrylamide. Autoradiography (45Ca) will be used to identify nuclei or regions in brains from acrylamide-treated rats which exhibit changes in calcium uptake and/or retention. Such areas (e.g. cerebellum) might represent structures which are selectively damaged by acrylamide and therefore are importantly involved in the manifestation of neurotoxicity. Alterations in the subcellular distribution of calcium and other ions produced by acrylamide will be determined using x-ray microanalysis. With this technique it is possible to measure ion concentrations in mitochondria and other subcellular organelle. Acrylamide neurotoxicity might be mediated by the inhibitory effect of calcium on mitochondrial respiration. Therefore, oxygen uptake will be measured using a Clark's oxygen electrode in nervous tissues and in nerve cell cultures exposed to acrylamide. The long range goal of this research is to identify the role of calcium in the distal axonpathy produced by acrylamide and other neurotoxins. Results from this research might implicate an involvement of calcium in human disease states (e.g. infantile neuroaxonal dystrophy) which are associated with neuropathic changes similar to those induced by acrylamide.