Rm. Lopachin et Ej. Lehning, MECHANISM OF CALCIUM-ENTRY DURING AXON INJURY AND DEGENERATION, Toxicology and applied pharmacology, 143(2), 1997, pp. 233-244
Axon degeneration is a hallmark consequence of chemical neurotoxicant
exposure (e.g., acrylamide), mechanical trauma (e.g., nerve transectio
n, spinal cord contusion), deficient perfusion (e.g., ischemia, hypoxi
a), and inherited neuropathies (e.g., infantile neuroaxonal dystrophy)
. Regardless of the initiating event, degeneration in the PNS and CNS
progresses according to a characteristic sequence of morphological cha
nges. These shared neuropathologic features suggest that subsequent de
generation, although induced by different injury modalities, might evo
lve via a common mechanism. Studies conducted over the past two decade
s indicate that Ca2+ accumulation in injured axons has significant neu
ropathic implications and is a potentially unifying mechanistic event.
However, the route of Ca2+ entry and the involvement of other relevan
t ions (Na+, K+) have not been adequately defined. In this overview, w
e discuss evidence for reverse operation of the Na+-Ca2+ exchanger as
a primary route of Ca2+ entry during axon injury. We propose that dive
rse injury processes (e.g., axotomy, ischemia, trauma) which culminate
in axon degeneration cause an increase in intraaxonal Na+ in conjunct
ion with a loss of Ki and axolemmal depolarization. These conditions f
avor reverse Na+-Ca2+ exchange operation which promotes damaging extra
axonal Ca2+ entry and subsequent Ca2+-mediated axon degeneration. Deci
phering the route-bf axonal Ca2+ entry is a fundamental step in unders
tanding the pathophysiologic processes induced by chemical neurotoxica
nts and other types of nerve damage. Moreover, the molecular mechanism
of Ca2+ entry can be used as a target for the development of efficaci
ous pharmacotherapies that might be useful in preventing or limiting i
rreversible axon injury. (C) 1991 Academic Press.