Eb. George et al., AXOTOMY-INDUCED AXONAL DEGENERATION IS MEDIATED BY CALCIUM INFLUX THROUGH ION-SPECIFIC CHANNELS, The Journal of neuroscience, 15(10), 1995, pp. 6445-6452
We examined the role of extracellular calcium entry, the possible invo
lvement of axonal calcium channels, and the potential protective effec
t of calcium channel and calpain antagonists in axotomy-induced axonal
degeneration using murine dorsal root ganglia in cell culture. We fou
nd that calcium entry is both necessary and sufficient to induce axona
l degeneration after axotomy, and may be inhibited by cobalt, manganes
e, dihydropyridines, and bepridil. Tetrodotoxin and omega-conotoxin ar
e ineffective in preventing axonal degeneration. The activation of cal
pains also appears to be necessary and sufficient for axonal degenerat
ion to proceed, and can be blocked with membrane-permeant leupeptin an
alogs and the oxirane aloxistatin. Although other calcium-activated ev
ents may occur, it appears that inhibition of calpain is sufficient to
preserve the axon at the light microscope lever, and to prevent axona
l cytoskeleton degradation as detected by immunofluorescent staining.
Our results suggest that axonal degeneration after axotomy involves th
e following sequence of events: (1) a lag-period after axotomy prior t
o the onset of axonal degeneration, (2) entry of calcium into the axon
through an intact axolemma via a calcium-specific ion transport mecha
nism, (3) activation of calcium-dependent effector molecules such as c
alpains, (4) degradation of the axonal cytoskeleton. The details of th
e second step require further elucidation, and are of particular inter
est because this step is a potential target for therapies directed tow
ards peripheral neuropathies.