MOLECULAR MECHANISMS OF HEXACARBON INDUCED AXON ATROPHY

描述：甲基的神经毒性代谢物2，5-己二酮(HD) 正丁基酮和正己烷，可造成神经损伤，被归类为 中枢-外周远端轴索病症。它的形态特征是 神经病是巨大的神经丝状轴突肿胀，它一直是 实质力学研究的重点。然而，其他证据表明 轴突萎缩是一种潜在的重大致病事件。研究 已经证明了在周围神经中 HD处理的大鼠萎缩是一种普遍的、不依赖于路径的现象 可能具有功能性和机械性的含义。相比之下， 轴突肿胀的发展取决于轴突的长度和路径 曝光。据推测，萎缩症是 伽玛二酮诱导的神经病及其通过减少外周神经的作用 神经丝蛋白的合成与翻译后神经丝蛋白的可能缺陷 磷酸化。这项研究项目的长期目标是 评估轴突萎缩的神经毒理学相关性并确定 相应的分子机制。以下是具体目标 建议研究轴突萎缩在伽玛二酮中的作用 神经毒性：1)。轴索肿胀的药代动力学基础 萎缩将使用两种不同的IP进行评估。配药率和 测定血清HD水平。2)研究旨在确定 萎缩是否由核周神经营养因子亚单位减少所介导 综合。3)。高密度脂蛋白中毒对神经营养因子磷酸化和蛋白合成的影响 磷酸基团的周转将在背根节和 坐骨神经。如果观察到磷酸化的变化，我们将 确定这种效应是否由HD诱导的磷酸盐变化所介导 或者是激酶的活性。拟议的项目可以提供新的信息 关于六碳轴索病的机制。此外，这一点 该提案可能会对其他有毒化学品产生广泛的影响 (丙烯酰胺、二硫化碳)与疾病进程(糖尿病)相关 伴有轴突萎缩。

DESCRIPTION: 2,5-Hexanedione (HD), the neurotoxic metabolite of methyl n-butyl ketone and n-hexane, causes nerve damage classified as a central-peripheral distal axonopathy. The morphological hallmark of this neuropathy is giant neurofilamentous axonal swellings which have been the focus of substantial mechanistic research. However, other evidence suggests that axonal atrophy is a potentially significant pathogenic event. Studies from this laboratory have demonstrated that in peripheral nerve of HD-treated rats atrophy was a prevalent, route-independent phenomenon that might have functional and mechanistic implications. In contrast, the development of axonal swelling was dependent upon length and route of exposure. It is hypothesized that atrophy is an essential component of gamma-diketone-induced neuropathy and is mediated by reduced perikaryal neurofilament (NF) synthesis and possibly deficient posttranslational NF phosphorylation. The long-term objectives of this research project are to evaluate the neurotoxicological relevance of axonal atrophy and determine the corresponding molecular mechanism. The following Specific Aims are proposed to investigate the role of axonal atrophy in gamma-diketone neurotoxicity: 1). The pharmacokinetic basis of axonal swellings and atrophy will be assessed using two different i.p. dosing rates and measurements of serum HD levels. 2) Studies have been designed to determine whether atrophy is mediated by a reduction in perikaryal NF subunit synthesis. 3). The effects of HD intoxication on NF phosphorylation and phosphate group turnover will be quantitated in dorsal root ganglion and sciatic nerve. If alterations in phosphorylation are observed, we will determine whether this effect is mediated by HD-induced changes in phosphate or kinase activity. The proposed project could provide new information regarding the mechanism of hexacarbon axonopathy. In addition, this proposal might have broad-based implications for other toxic chemicals (acrylamide, carbon disulfide) and disease processes (diabetes) associated with axonal atrophy.