The mechanisms of acrylamide axonopathy

The neurotoxic property of acrylamide has been studied for more than 30 years. Recognition that the underlying lesion involves distal retrograde degeneration of long and large-diameter axons demonstrated that acrylamide neuropathy belongs to the class of central-peripheral distal axonopathies. This is a relatively common response of the nervous system found in a large number of unrelated toxic-metabolic states. The ready availability of pure acrylamide and the ability to reproduce a reliable model of acrylamide neuropathy in laboratory animals encouraged many investigators to focus on this disorder as a paradigm with which to study the cellular and biochemical mechanisms underlying distal axonopathies. The discovery that abnormalities of energy-dependent axonal transport are associated with nerve fiber degeneration led investigators to explore the possibility that energy flux in axons is perturbed by the action of acrylamide. This hypothesis has proved as yet untestable by direct means, due to an inability to separate glial contributions to energy production from those of the axon. Indirect means of addressing this hypothesis have, however, yielded data suggestive of a role for altered glycolysis in the etiology of acrylamide axonopathy. However, it is becoming apparent that, if diminished glycolytic flux is involved in the etiology of axonopathy, it is unlikely to be the sole pathologic mechanism and may in fact represent only one facet of a complex series of biochemical events underlying axonopathy. A recent hypothesis has suggested that alterations in axon-perikaryal interactions may underlie acrylamide-induced axonopathy. Evidence exists to indicate that alterations in the retrograde axonal transport of axon-derived maintenance- or repair-initiating factors may prevent or attenuate the perikaryal responses necessary to repair and maintain the distal axon in the presence of acrylamide. Thus, acrylamide-induced axonopathy may be the result of at least two biochemical lesions: (a) A relatively non-specific axonal lesion that may be the inhibition of glycolytic enzyme activity or some other axon lesion resulting from the interaction of acrylamide with sulfhydryl, amino, and/or hydroxyl moieties associated with axonal constituents. (b) Inhibition of perikaryal-mediated axon repair and maintenance mechanisms that could occur as a result of alterations in retrograde axonal transport of one or more lesion-associated factors or as a result of a direct action of acrylamide on the perikaryon. A third hypothesis suggests that a direct action of acrylamide on the neuronal perikaryon alone may result in a generalized, non-specific metabolic lesion that stresses the neuron to a point where the distal end can no longer be maintained. Regardless of the actual mechanism of acrylamide-induced axonopathy, recent investigations by several laboratories have provided new and exciting insights into the possible mechanism of distal axonopathy, the means by which axon-perikaryal communication occurs, and the manner in which the perikaryon responds to axon damage. In addition to the obvious significance that understanding mechanisms of toxin-induced peripheral nerve degeneration has to the toxicologist, toxic neuropathy may be a means by which the basic mechanisms underlying comparable human neurodegenerative disorders may profitably be studied.