γ-Diketone neuropathy: Axon atrophy and the role of cytoskeletal protein adduction

Richard M. LoPachin, Anthony P. DeCaprio

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Multifocal giant neurofilamentous axonal swellings and secondary distal degeneration have been historically considered the hallmark features of γ-diketone neuropathy. Accordingly, research conducted over the past 25 years has been directed toward discerning mechanisms of axonal swelling. However, this neuropathological convention has been challenged by recent observations that swollen axons were an exclusive product of long-term 2,5-hexanedione (HD) intoxication at lower daily dose-rates (e.g., 175 mg/kg/day); that is, higher HD dose-rates (e.g., 400 mg/kg/day) produced neurological deficits in the absence of axonal swellings. The observation that neurological toxicity can be expressed without axonal swelling suggests that this lesion is not an important pathophysiological event. Instead, several research groups have now shown that axon atrophy is prevalent in nervous tissues of laboratory animals intoxicated over a wide range of HD dose-rates. The well-documented nerve conduction defects associated with axon atrophy, in conjunction with the temporal correspondence between this lesion and the onset of neurological deficits, strongly suggest that atrophy has pathophysiological significance. In this commentary, we present evidence that supports a pathognomonic role for axon atrophy in γ-diketone neuropathy and suggests that the functional consequences of this lesion mediate the corresponding neurological toxicity. Previous research has demonstrated that HD interacts with proteins via formation of pyrrole adducts. We therefore discuss the possibility that this chemical process is essential to the mechanism of atrophy. Evidence presented in this review suggests that "distal axonopathy" is an inaccurate classification and future nosological schemes should be based on the apparent primacy of axon atrophy.

Original languageEnglish (US)
Pages (from-to)20-34
Number of pages15
JournalToxicology and Applied Pharmacology
Volume199
Issue number1
DOIs
Publication statusPublished - Aug 15 2004

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Keywords

  • 2,5-Hexanedione
  • Axon atrophy
  • Axon swellings
  • Distal axonopathy
  • Neurofilament adduction
  • γ-diketone neuropathy

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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