title: Toxic neuropathies: Mechanistic insights based on a chemical perspective.
abstract: 2,5-Hexanedione (HD) and acrylamide (ACR) are considered to be prototypical among chemical toxicants that cause central-peripheral axonopathies characterized by distal axon swelling and degeneration. Because the demise of distal regions was assumed to be causally related to the onset of neurotoxicity, substantial effort was devoted to deciphering the respective mechanisms. Continued research, however, revealed that expression of the presumed hallmark morphological features was dependent upon the daily rate of toxicant exposure. Indeed, many studies reported that the corresponding axonopathic changes were late developing effects that occurred independent of behavioral and/or functional neurotoxicity. This suggested that the toxic axonopathy classification might be based on epiphenomena related to dose-rate. Therefore, the goal of this mini-review is to discuss how quantitative morphometric analyses and the establishment of dose-dependent relationships helped distinguish primary, mechanistically relevant toxicant effects from non-specific consequences. Perhaps more importantly, we will discuss how knowledge of neurotoxicant chemical nature can guide molecular-level research toward a better, more rational understanding of mechanism. Our discussion will focus on HD, the neurotoxic γ-diketone metabolite of the industrial solvents n-hexane and methyl-n-butyl ketone. Early investigations suggested that HD caused giant neurofilamentous axonal swellings and eventual degeneration in CNS and PNS. However, as our review will point out, this interpretation underwent several iterations as the understanding of γ-diketone chemistry improved and more quantitative experimental approaches were implemented. The chemical concepts and design strategies discussed in this mini-review are broadly applicable to the mechanistic studies of other chemicals (e.g., n-propyl bromine, methyl methacrylate) that cause toxic neuropathies.
authors.affiliation: Department of Anesthesiology, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY 10467, United States. Electronic address: richard.lopachin@einstein.yu.edu.
authors.forename: Richard M
authors.initials: RM
authors.lastname: LoPachin
authors.affiliation: Department of Chemistry, Iona College, 402 North Avenue, New Rochelle, NY 10804, United States.
authors.forename: Terrence
authors.initials: T
authors.lastname: Gavin
mesh_terms: D001369:Axons / Q000187:drug effects / Q000473:pathology; D002493:Central Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D004785:Environmental Pollutants / Q000633:toxicity*; D006588:Hexanones / Q000633:toxicity*; D006801:Humans; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology
chemical_list: D004785:Environmental Pollutants; D006588:Hexanones; C011269:2,5-hexanedione
keywords: 2,5-Hexanedione; Acrylamide; Central–peripheral distal axonopathy; Dying back neuropathy; Neurotoxicity; Peripheral neuropathy