MOLECULAR MECHANISMS OF HEXACARBON INDUCED AXON ATROPHY

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date1/1/975/31/08

Funding

  • National Institute of Environmental Health Sciences: $108,370.00
  • National Institute of Environmental Health Sciences: $271,573.00
  • National Institute of Environmental Health Sciences: $335,288.00
  • National Institute of Environmental Health Sciences
  • National Institute of Environmental Health Sciences: $260,606.00
  • National Institute of Environmental Health Sciences: $261,047.00
  • National Institute of Environmental Health Sciences
  • National Institute of Environmental Health Sciences: $345,302.00
  • National Institute of Environmental Health Sciences

ASJC

  • Clinical Neurology
  • Molecular Biology
  • Pharmacology

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