MECHANISM OF CALCIUM-ENTRY DURING AXON INJURY AND DEGENERATION

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.