Pathogenesis of axonal degeneration: parallels between Wallerian degeneration and vincristine neuropathy.
Peripheral neuropathies and Wallerian degeneration share a number of pathological features; the most prominent of which is axonal degeneration. We asked whether common pathophysiologic mechanisms are involved in these 2 disorders by directly comparing in vitro models of axonal degeneration after axotomy or exposure to the neurotoxin vincristine. Embryonic rat dorsal root ganglia (DRG) were allowed to extend neurites for 5 days in culture, and then were either axotomized or exposed to 0.01 microM vincristine. Neurites universally degenerated by 3 days after axotomy or after 6 days of vincristine exposure. The neuroprotective effects of a low calcium environment or pharmacologic inhibition of the cysteine protease calpain were compared in these 2 models of axonal degeneration. Addition of EGTA or growth in zero-calcium media provided significant protection against axonal degeneration after either axotomy or vincristine exposure. Treatment with the experimental calpain inhibitor AK295 was equally protective in both models. Chronic exposure to AK295 was not toxic to the cultures. These data suggest that common mechanisms involving calcium and calpains are involved in both axotomy-induced and vincristine-induced axonal degeneration. In addition, calpain inhibition may provide a strategy for preventing axonal degeneration and preserving neurologic function in a variety of PNS and CNS disorders.
Wang
M S
MS
Department of Neurology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Wu
Y
Y
Culver
D G
DG
Glass
J D
JD
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D001369:Axons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D019771:Axotomy; D002154:Calpain / Q000378:metabolism; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014750:Vincristine / Q000633:toxicity*; D014855:Wallerian Degeneration / Q000139:chemically induced / Q000473:pathology*
D000972:Antineoplastic Agents, Phytogenic; D002614:Chelating Agents; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; C090138:AK 295; D004533:Egtazic Acid; D014750:Vincristine; D002154:Calpain