CALCIUM AND ACRYLAMIDE NEUROTOXICITY

丙烯酰胺（ACR）在化工领域有着广泛的应用。 实验室动物和人暴露于ACR导致神经损伤 归类为中枢外周远端轴突病。 形态 这种轴突病的特征是结旁肿胀和变性 远端神经纤维 本研究项目的长期目标 目的是：1）确定ACR诱导的远端轴突肿胀的机制， 2）确定雪旺细胞在这一过程中的作用 退化过程 周围神经的广泛研究 元素分布和酶活性进行了研究， 当前融资期。 基于这项工作，假设ACR 导致Na/Ca交换器的反向操作，其介导Ca进入 敏感的轴突 交换器反转是由 轴突内Na，这反过来又是Na/K-ATP酶减少的结果 递送至远端轴突部位。 钙的轴浆积累启动了一个 损伤级联，最终导致远端轴突肿胀和变性。 下面的特定目标是为了测试这种启发式方法而设计的 模型1)ACR对原位Na/K-ATP酶功能的影响， 通过测定铷在有髓轴突中的分布进行评价 和雪旺细胞，并通过评估神经节苷脂的能力， ACR诱导的元素破坏。2)Na/K-ATP酶转运和空间 将在对照组和ACR组的外周神经中测定分布。 治疗的老鼠3)蛋白激酶C活性增加的可能作用 将检查ACR的神经毒性。4)将进行研究， 确定Na/Ca交换器的反向操作是否可以促进Ca 入境5)ACR对电压门控性Na+和K+通道的影响将是 测定6)实验被设计来确定施旺是否 细胞被ACR损伤或对初级轴突损伤有反应。7)的 结间元素变化的神经毒理学特异性 确定。 ACR神经毒性是化学物质的原型损伤模型 导致远端轴突变性（DAD）。 由于DAD是最常见的 轴突对化学物质的反应，确定ACR轴突病的机制 可能与其他DAD神经毒剂有关 此外，建议 研究可能会提出一些药物治疗方法， 治疗DAD

Acrylamide (ACR) has broad application in various chemical industries. Exposure of laboratory animals and man to ACR causes nerve damage classified as a centralperipheral distal axonopathy. The morphological characteristics of this axonopathy are paranodal swelling and degeneration of distal nerve fibers. The long-term objectives of this research project are to: 1) determine the mechanism of ACR-induced distal axon swelling and degeneration and, 2) determine the role of Schwann cells in this degenerative process. Extensive investigations of peripheral nerve elemental distribution and enzyme activity have been conducted during the current funding period. Based on this work it is hypothesized that ACR causes reverse operation of the Na/Ca-exchanger which mediates Ca entry in sensitive axons. Exchanger reversal is brought about by elevation of intraaxonal Na which, in turn, is a consequence of reduced Na/K-ATPase delivery to distal axon sites. Axoplasmic accumulation of Ca initiates an injury cascade that culminates in distal axon swelling and degeneration. The following Specific Aims have been designed to test this heuristic model. 1) The effects of ACR on in situ Na/K-ATPase function will be evaluated by determining the disposition of rubidium in myelinated axons and Schwann cells and by assessing the ability of gangliosides to affect ACR-induced elemental disruption. 2) Na/K-ATPase transport and spatial distribution will be determined in peripheral nerve of control and ACR- treated rats. 3) The possible role of increased protein kinase C activity in ACR neurotoxicity will be examined. 4) Studies will be conducted to determine whether reverse operation of the Na/Ca-exchanger can promote Ca entry. 5) The effects of ACR on voltage-gated Na+ and K+ channels will be determined. 6) Experiments have been designed to determine whether Schwann cells are injured by ACR or are responding to primary axon injury. 7) The neurotoxicological specificity of internodal elemental changes will be ascertained. ACR neurotoxicity is a prototypic injury model for chemicals that produce distal axon degeneration (DAD). Since DAD is the most common response of axons to chemicals, determining the mechanism of ACR axonopathy might have relevance to other DAD neurotoxicants. Moreover, proposed research might suggest pharmacotherapeutic modalities useful in the treatment of DAD.