Abstract
After a traumatic injury to the central nervous system, the distal stumps of axons undergo Wallerian degeneration (WD), an event that comprises cytoskeleton and myelin breakdown, astrocytic gliosis, and overexpression of proteins that inhibit axonal regrowth. By contrast, injured neuronal cell bodies show features characteristic of attempts to initiate the regenerative process of elongating their axons. The main molecular event that leads to WD is an increase in the intracellular calcium concentration, which activates calpains, calcium-dependent proteases that degrade cytoskeleton proteins. The aim of our study was to investigate whether preventing axonal degeneration would impact the survival of retinal ganglion cells (RGCs) after crushing the optic nerve. We observed that male Wistar rats (weighing 200-400 g; n=18) treated with an exogenous calpain inhibitor (20 mM) administered via direct application of the inhibitor embedded within the copolymer resin Evlax immediately following optic nerve crush showed a delay in the onset of WD. This delayed onset was characterized by a decrease in the number of degenerated fibers (P<0.05) and an increase in the number of preserved fibers (P<0.05) 4 days after injury. Additionally, most preserved fibers showed a normal G-ratio. These results indicated that calpain inhibition prevented the degeneration of optic nerve fibers, rescuing axons from the process of axonal degeneration. However, analysis of retinal ganglion cell survival demonstrated no difference between the calpain inhibitor- and vehicle-treated groups, suggesting that although the calpain inhibitor prevented axonal degeneration, it had no effect on RGC survival after optic nerve damage.
Highlights
After an insult, neurons from the adult optic nerve do not spontaneously regenerate their axons beyond the injury site [1]
Our preliminary data indicated that a calpain inhibitor administered during the early stages of Wallerian degeneration (WD) prevented axonal degeneration compared with vehicle-treated nerves subjected to the same trauma
Massive cell death occurs within 2 weeks after injury, when 60 to 70% of retinal ganglion cells (RGCs) die, and 1 month after injury, when the rate of cell survival falls to only 5% [21]
Summary
Neurons from the adult optic nerve do not spontaneously regenerate their axons beyond the injury site [1]. At day 7 after injury, while RGCs are still viable and show characteristics indicative of the regenerative process, all crushed axons at the distal stump have already undergone full degeneration [4,7,9]. This axonal disintegration process is mediated by the activation of calcium-dependent proteases, such as calpains, that target cytoskeleton proteins, especially neurofilaments, for degradation [10]
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