Slow axonal transport in acrylamide neuropathy: different abnormalities produced by single-dose and continuous administration

Abstract

Alterations in axonal caliber and neurofilament content have been associated with altered neurofilament transport in several models of neurofibrillary degeneration. Acrylamide intoxication provides a prototype of distal axonal degeneration, the most frequent pattern of axonal pathology in human and experimental neurotoxic injury. Neurofibrillary changes are a variable and often minor aspect of the early pathological changes observed in acrylamide intoxication, and previous studies of slow axonal transport have produced conflicting results. In this study, we have correlated slow axonal transport, specifically neurofilament transport, with structural changes in the sciatic nerve complex of rats exposed to acrylamide. To study direct toxic effects of acrylamide, young rats were given a single dose of acrylamide (75 mg/kg, i.p.). A second group received daily injections of acrylamide at a lower dose (30 mg/kg, i.p.) in order to study animals with established acrylamide neuropathy. The slow component of axonal transport was labeled by intraspinal injections of [35S] methionine. Transport of individual slow component polypeptides was compared to profiles obtained from age-matched controls. Similarly intoxicated rats were perfused for morphometric and morphological studies. Results demonstrate that two different abnormalities of the slow component of axonal transport arise at different stages during the development of experimental acrylamide neuropathy. Both patterns of altered transport have structural correlates which reflect the changes in neurofilament transport. Following a single high dose, there was a modest retardation of the leading edge of the slow component. At this time, neurofilaments accumulated in proximal axons with formation of axonal swellings. During chronic administration, when distal axonal degeneration was present, the proportion of neurofilaments in the slow component was markedly reduced, and there was prominent loss of caliber in proximal axons. We suggest that these early changes represent a direct toxic effect of acrylamide on slow transport, whereas the later changes reflect reordering of slow transport as a neuronal response to toxin-induced axonal injury. This latter effect is of sufficient magnitude to obscure the acrylamide-induced retardation of slow transport.

Nitric oxide prevents axonal degeneration by inducing HIF-1–dependent expression of erythropoietin

“…Acrylamide-induced peripheral neuropathy is a well-established, reproducible rodent model of distal axonal degeneration (21). Acrylamide is known to interfere with slow axonal transport (22). Oral administration of acrylamide to rodents causes distal degeneration of motor axons, resulting in distal limb weakness (14,23).…”

Motor Neuron Disease Occurring in a Mutant Dynactin Mouse Model Is Characterized by Defects in Vesicular Trafficking

“…In addition to defects in vesicular transport, perturbations in axonal transport have been hypothesized to play a role in the pathogenesis of human diseases, including ALS (Price et al, 1975;Griffin and Price, 1976), and have been shown to occur in various animal models (Price et al, 1975;Griffin and Price, 1976;Griffin et al, 1978;Gold et al, 1985;Collard et al, 1995;Williamson and Cleveland, 1999). In studies of mutant SOD1 (Cu/Zn superoxide dismutase) mice, disruption of transport has been shown to antedate the onset of clinical signs (Williamson and Cleveland, 1999).…”

Scientific Opinion on acrylamide in food

“…The neurotoxic action of AA was suggested to be due to effects on cells of the central and peripheral nervous system including changes in cellular metabolism (Howland et al, 1980;Brimijoin and Hammond,1985;Medrano and LoPachin, 1989;Exon, 2006), changes in gene transcription and protein synthesis (Cavanagh and Nolan, 1982a,b;Cavanagh, 1982;Cavanagh and Gysbers, 1983;Bisby and Redshaw, 1987;Lin et al, 2000;El-Alfy et al, 2011;Seale et al, 2012), effects on neurotransmitter levels and turn-over (Dixit et al, 1981;Uphouse and Russell, 1981;Aldous et al, 1983;Shi et al, 2012), binding to cellular proteins including damage to microtubular and neurofilamental proteins (Hashimoto and Aldridge, 1970;Tanii and Hashimoto, 1983;Carrington et al, 1991;Reagan et al, 1994;Abou-Donia, 1996, 1997;Lapadula et al, 1989;Xiwen et al, 1992), changes in ion distribution (Lehning et al, 1998;LoPachin and Lehning, 1994), and axonal transport (Chretien et al, 1981;Miller and Spencer, 1984;Gold et al, 1985;Moretto and Sabri, 1988;Logan and McLean, 1988;Harry et al, 1989;Sabri and Spencer, 1990;Martenson et al, 1995;Sickles et al, 1995Sickles et al, ,1996Stone et al, 2001). However, the minimal effects of AA-treatment, by up to a maximally tolerated dose, on: (i) gene expression related to cholinergic, noradrenergic, dopaminergic, GABAergic, or glutamatergic neurotransmitter systems; (ii) neurotransmitter levels related ...…”