Pathogenesis of axonal degeneration: Parallels between Wallerian degeneration and vincristine neuropathy

Peripheral neuropathies and Wallerian degeneration share a number of pathol ogical features; the most prominent of which is axonal degeneration. We ask ed whether common pathophysiologic mechanisms are involved in these 2 disor ders by directly comparing in vitro models of axonal degeneration after axo tomy or exposure to the neurotoxin vincristine. Embryonic rat dorsal root g anglia (DRG) were allowed to extend neurites for 5 days in culture, and the n were either axotomized or exposed to 0.01 mu M. vincristine. Neurites uni versally degenerated by 3 days after axotomy or after 6 days of vincristine exposure. The neuroprotective effects of a low calcium environment or phar macologic inhibition of the cysteine protease calpain were compared in thes e 2 models of axonal degeneration. Addition of EGTA or growth in zero-calci um media provided significant protection against axonal degeneration after either axotomy or vincristine exposure. Treatment with the experimental cal pain inhibitor AK295 was equally protective in both models. Chronic exposur e to AK295 was not toxic to the cultures. These data suggest that common me chanisms involving calcium and calpains are involved in both axotomy-induce d and vincristine-induced axonal degeneration. In addition, calpain inhibit ion may provide a strategy for preventing axonal degeneration and preservin g neurologic function in a variety of PNS and CNS disorders.