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.

长期接触丙烯酰胺会导致骨骼肌无力 伴有远端轴突病变。 造成这种情况的生化损伤 神经元损伤尚未确定。 最近的研究表明， 各种损伤引起的神经元内钙含量增加 过程（例如化学、疾病）是造成结果的原因 神经元损伤和/或死亡。 因此，丙烯酰胺可能会造成伤害 导致细胞膜“渗漏”，从而允许 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 确定钙浓度是否逐渐增加 与丙烯酰胺中毒暂时相关。 这些研究将涉及 使用来自丙烯酰胺处理的大鼠的神经组织和神经细胞 暴露于这种神经毒素的培养系统。 具体来说，初步研究 将采用原子吸收分光光度法来测量 丙烯酰胺引起的总钙浓度变化。 变化 钙水平将与发育的时间相关 丙烯酰胺引起的神经元损伤。 将使用放射自显影 (45Ca) 鉴定经丙烯酰胺处理的大鼠大脑中的细胞核或区域 表现出钙吸收和/或保留的变化。 此类区域（例如 小脑）可能代表被选择性损坏的结构 丙烯酰胺因此重要地参与了 神经毒性。 钙和亚细胞分布的改变 丙烯酰胺产生的其他离子将使用 X 射线测定 微观分析。 利用该技术可以测量离子 线粒体和其他亚细胞器中的浓度。 丙烯酰胺 神经毒性可能是通过钙的抑制作用介导的 线粒体呼吸。 因此，将使用以下方法测量摄氧量 神经组织和神经细胞培养物中的克拉克氧电极 接触丙烯酰胺。 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变中的作用 其他神经毒素。 这项研究的结果可能暗示 钙与人类疾病状态的关系（例如婴儿神经轴突 营养不良），与类似的神经病变相关 由丙烯酰胺引起。