THE RELEVANCE OF AXONAL SWELLINGS AND ATROPHY TO GAMMA-DIKETONE NEUROTOXICITY - A FORUM POSITION PAPER

Traditionally gamma-diketone neuropathy is classified as a distal axon opathy and has been characterized by giant axonal swellings in CNS and PNS tissues. These swellings contain neurofilamentous masses and are associated with thinning and retraction of the myelin sheath. It has b een proposed that this axonopathy is caused by direct gamma-diketone m odification of neurofilaments (NFs) involving pyrrolation of epsilon-a mino groups on NF lysyl residues and possibly secondary autoxidation o f the pyrrole rings with creation of covalent NF-NF crosslinks. Neurof ilaments are thought to undergo chemical modification as they progress along the axonal axis and, eventually, accumulate at distal nodes of Ranvier where their proximodistal movement is impeded. Development of swelling presumably initiates axonal degeneration and subsequent funct ional deficits. However, other research suggests that axonal swellings are a non-specific effect related to subchronic gamma-diketone exposu re. Such evidence draws into question the mechanistic relevance of the se swellings. In contrast, research conducted over the past decade ind icates axonal atrophy is a specific morphologic component of gamma-dik etone neuropathy which might have both functional and mechanistic impo rtance. In this overview the potential neurotoxicological significance of both axonal swellings and atrophy are evaluated critically Based o n the evidence to be presented, we propose that axonal atrophy is the morphological consequence of the molecular mechanism of gamma-diketone neuropathy. Accordingly, several mechanistic scenarios related to the development of atrophy will be discussed. It is hoped that this Forum will stimulate scientific debate and initiate laboratory investigatio ns which will either confirm or refute the involvement of axonal atrop hy in gamma-diketone neurotoxicity. Investigating gamma-diketone atrop hy might provide insight into the mechanism of other toxic axonopathie s which are also associated with reduced axon caliber; e.g., acrylamid e and carbon disulfide neuropathies. (C) 1997 Inter Press, Inc.