MOLECULAR MECHANISMS OF HEXACARBON INDUCED AXON ATROPHY

性状：2，5-己二酮（HD），甲基的神经毒性代谢产物 正丁基酮和正己烷，导致神经损伤，被归类为 中枢-外周远端轴突病 这种生物的形态学特征 神经病是巨大的神经丝轴突肿胀，这一直是 实质性机制研究的焦点。 然而，其他证据表明， 轴突萎缩是一种潜在的重要致病事件 研究 在这个实验室已经证明，在周围神经， HD处理的大鼠萎缩是一种普遍的、途径无关的现象， 可能会有功能和机制上的影响。 而反观 轴突肿胀的发展取决于轴突的长度和途径。 exposure. 据推测，萎缩是一个重要组成部分， γ-二酮诱导的神经病，并通过减少核周 神经丝（NF）合成和可能缺乏翻译后NF 磷酸化 本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。 以下具体目标是 建议研究轴突萎缩在γ-二酮 神经毒性：1）。 轴突兴奋的药代动力学基础， 将使用两种不同的腹膜内给药速率评估萎缩， 测量血清HD水平。 2)研究旨在确定 萎缩是否由核周NF亚基减少介导 合成. 3）。 HD中毒对NF磷酸化和NF-κ B的影响 将在背根神经节中定量磷酸基团周转， 坐骨神经 如果观察到磷酸化的改变， 确定这种效应是否由HD诱导的磷酸盐变化介导 或激酶活性。 拟议的项目可以提供新的信息 关于六碳轴突病的机制。 另外这款 该提案可能对其他有毒化学品产生广泛影响 （丙烯酰胺、二硫化碳）和疾病过程（糖尿病）相关 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.