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.
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