CALCIUM AND ACRYLAMIDE NEUROTOXICITY

丙烯酰胺(ACR)在各种化学工业中有着广泛的应用。 实验动物和人暴露于ACR会导致神经损伤 被归类为中心性外周性远端轴索病。形态上的 本病的特点是结旁肿胀和变性。 远端神经纤维。这项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； 变性和，2)确定雪旺细胞在此过程中的作用 退化过程。对周围神经的广泛研究 元素分布和酶活性在实验期间进行了研究。 当前资金期限。根据这项工作，我们假设ACR 导致钠/钙交换器的反向操作，该交换器介导钙进入 敏感的轴突。交易所反转由以下因素引起： 轴突内钠，进而是Na/K-ATPase降低的结果 送到远端轴突部位。钙的轴浆积累启动了一种 损伤级联，最终导致远端轴突肿胀和变性。 已经设计了以下具体目标来测试这个启发式方法 模特。1)ACR对在位Na/K-ATPase功能的影响 通过测定有髓轴突中Rb的分布来评估 和雪旺细胞，并通过评估神经节苷脂影响 ACR诱导的元素分裂。2)Na/K-ATPase转运和空间分布 将测定对照组和ACR在周围神经中的分布。 治疗过的老鼠。3)蛋白激酶C活性升高的可能作用 在ACR中，将检测神经毒性。4)将进行研究以 确定Na/Ca交换器反向操作是否能促进钙离子 进入。5)ACR对电压门控Na+和K+通道的影响 下定决心。6)已经设计了实验来确定施万恩 细胞受到ACR的损伤或对初级轴突损伤有反应。7) 结间元素改变的神经毒理学特异性将是 已经确定了。ACR神经毒性是一种典型的化学品损伤模型 会导致远端轴突变性(DAD)。因为爸爸是最常见的 轴突对化学物质的反应，确定ACR轴索病的机制 可能与其他DAD神经毒剂有关。此外，建议 研究可能会提示药物治疗方式对 对父亲的治疗。

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.