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Evidence suggests the morphologic hallmark of gamma-diketone neuropathy is axon atrophy and that this effect is associated with reduced neurofilament (NF) subunit protein content (Toxicol Appl Pharmacol 2000;165:141-7). To investigate the mechanism of diminished NF content, subunit (NF-L, -M and -H) gene expression was quantified in dorsal root ganglion (DRG) of slightly affected and moderately intoxicated groups of rats exposed to 2,5-hexanedione (HD) at one of three daily dosing rates (175, 250 and 400 mg/kg per day). Results show that sensory ganglia from slightly affected rats exhibited no changes in gene expression, whereas at a moderate level of neurotoxicity, each dosing protocol was associated with small but significant reductions (approximately 20%) in mean NF subunit mRNA. This was not a generalized effect on expression of cytoskeletal components in sensory ganglia since tubulin message levels were not affected. Although the observed reduction in NF gene expression might be related to diminished levels of subunit proteins in peripheral nerve, the actual contribution is likely to be minimal. The magnitude of effect was small and did not correspond to the dose-rate dependent effect of HD on respective isotype proteins. The mechanism of gamma-diketone-induced axon atrophy is unknown but might involve local changes in axonal NF phosphorylation and degradation. |
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