2,5-Hexanedione (HD), the neurotoxic gamma-diketone metabolite of industrial solvents methyl n-butyl ketone and n-hexane, causes distal axonopathy. Giant neurofilamentous axonal swellings have been considered the morphologic hallmark and, accordingly, have been the focus of mechanistic research. However, published evidence suggests that axon atrophy, which also occurs in response to gamma-diketone intoxication, might be a significant pathogenic event. Quantitative morphometric studies conducted in the PI's laboratory during the current funding period showed that fiber atrophy in peripheral nerve of HD-intoxicated rats was a specific, prevalent effect that was temporally correlated to nerve conduction abnormalities and preceded behavioral defects. These findings implied atrophy was an essential pathophysiologic component of gamma-diketone-induced neurotoxicity. Parallel molecular determinations suggested that a reduction in neurofilament (NF) genetic expression and nerve content were the immediate cause of decreased axon caliber in HD exposed rats. In contrast, our research indicated giant axonal swellings were an epiphenomenon related to low dose HD exposure. The long-term objectives of this research project are to evaluate the neurotoxicological relevance of axonal atrophy and determine the corresponding molecular mechanism. How HD induces a selective reduction in NF synthesis is unknown. Research over the past decade has shown that mature axon caliber is maintained by target-derived neurotrophic factor influence on NF expression. Therefore, we hypothesize gamma-diketone-induced axon atrophy is produced by disruption of neuronal trophic factor signaling. This hypothesis will be tested according to the following specific aims: (1) The formation, activation and retrograde transport of neurotrophin (BDNF, NGF) signal complexes will be measured in peripheral nerve axis of gamma-diketone intoxicated rats. (2) gamma-Diketone influences on neurotrophin-trk receptor binding and neuronal internalization will be determined. (3) Assess the effects of gamma-diketone intoxication on neurotrophin-receptor complex stimulation of the Ras signal transduction pathway and activation of MAP kinase and subsequent nuclear translocation. The proposed research represents a new area of investigation into mechanisms of toxic axonopathies and has broad-based implications for acquired or inherited human neuropathies associated with fiber atrophy. In addition, our studies might suggest novel pharmacotherapies based on neurotrophin intervention or replacement.
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