Rm. Lopachin et Ej. Lehning, THE RELEVANCE OF AXONAL SWELLINGS AND ATROPHY TO GAMMA-DIKETONE NEUROTOXICITY - A FORUM POSITION PAPER, Neurotoxicology, 18(1), 1997, pp. 7-22
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.