ROLE OF CALCIUM IN ACRYLAMIDE NEUROTOXICITY

钙在丙烯酰胺神经毒性中的作用

• 批准号: 3251548
• 负责人: Richard Michael Lopachin
• 金额: $ 10万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 1989-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3251548
• 关键词: acrylamides; atomic absorption spectrometry; autoradiography; axon reaction; calcium channel blockers; cerebellum; electron microscopy; electron probe spectrometry; embryo /fetus; mitochondria; muscle disorders; neurotoxins; oxygen consumption; oxygen microelectrode; radiotracer; spinal cord; striated muscles; tissue /cell culture

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.

长期暴露于丙烯酰胺会导致骨骼肌无力相关 远端轴突病。 为此负责的生化病变 尚未确定神经元损伤。 最近的研究表明 多种伤害引起的神经内钙钙增加 过程（例如化学，疾病）负责由此导致 神经元损害和/或死亡。 因此，丙烯酰胺可能会通过 导致细胞膜变得“漏水”，从而允许涌入 细胞外钙和其他离子。 由此产生的增加 细胞质钙可能通过抑制引起神经细胞损伤 线粒体呼吸，通过破坏细胞骨架结构或通过 直接抑制轴突运输。 拟议的调查将 确定钙的浓度是否逐渐增加为 在时间上与丙烯酰胺中毒有关。 这些研究将涉及 使用丙烯酰胺治疗的大鼠和神经细胞的神经组织 暴露于这种神经毒素的培养系统。 具体而言，初始研究 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。 变更 钙水平将与临时相关 丙烯酰胺造成的神经元损害。 放射自显影（45CA）将使用 从丙烯酰胺处理的大鼠中鉴定核或大脑中的区域 表现出钙摄取和/或保留的变化。 这样的领域（例如 小脑）可能代表被选择性损害的结构 丙烯酰胺，因此重要地参与了 神经毒性。 钙的亚细胞分布的改变和 丙烯酰胺生产的其他离子将使用X射线确定 微分析。 通过这种技术，可以测量离子 线粒体和其他亚细胞细胞器的浓度。 丙烯酰胺 神经毒性可能是通过钙对抑制作用介导的 线粒体呼吸。 因此，将使用 神经组织和神经细胞培养中的克拉克氧电极 暴露于丙烯酰胺。 这项研究的远距离目标是确定 钙在丙烯酰胺和 其他神经毒素。 这项研究的结果可能暗示 钙参与人类疾病状态（例如，婴儿神经司长 营养不良）与类似于神经性变化的神经性变化有关 由丙烯酰胺诱导。