Calcium channel inhibition-mediated axonal stabilization improves axonal regeneration after optic nerve crush

Axonal projections are specialized neuronal compartments and the longest parts of neurons. Axonal degeneration is a common pathological feature in many neurodegenerative disorders, such as Parkinson's disease, amyotrophic lateral sclerosis, glaucoma, as well as in traumatic lesions of the central nervous system (CNS), such as spinal cord injury. In many neurological disorders, the axon is the first neuronal compartment affected, preceding the death of cell bodies. Following a lesion to the CNS, damaged axons degenerate and usually fail to regenerate past the point of the original injury, resulting in permanent deficits. The process of axonal degeneration is a regulated self-destructing cellular mechanism, which involves different steps. In the spinal cord and optic nerve, a focal traumatic lesion to the axons results in a sudden axonal disintegration extending for about 500 μm on both sides of the lesion that is termed acute axonal degeneration (Knoferle et al., 2010). After the fast disintegration of the adjacent parts of the lesioned axon during acute axonal degeneration, the rest of the axon remains morphologically stable within the following hours. At later time points the distal part of the axon undergoes Wallerian degeneration characterized by a widespread breakdown of the axonal cytoskeleton, destruction of internal organelles and ultimately axonal disintegration, while the proximal part of the axon starts the so-called slow dying back. At the molecular level, the initial axonal injury leads to a rapid calcium influx into the axon. Downstream of calcium, calpain proteases, which are key mediators of cytoskeletal degradation, are activated. In addition to calpain activation , autophagy is another important mechanism downstream of calcium that is increased in the course of axonal degeneration in the optic nerve and the spinal cord (Knoferle et al., 2010; Ribas et al., 2015). Channel-mediated influx of extracellular calcium is critical for initiating acute axonal degeneration, as calcium channel blockers prevent the early intra-axonal rise in calcium and almost completely prevent the following axonal degeneration. Moreover, addition of a calcium ionophore significantly increases the speed of axonal disintegration (Knoferle et al., 2010). Therefore, calcium influx is an important priming process regulating axonal degeneration. Numerous studies aiming at the improvement of outcome after traumatic axonal CNS lesions focused on neurorestorative approaches , such as stimulation of sprouting and axonal regeneration. The preservation of axonal integrity could be beneficial to improve such strategies. For example, increased axonal stabilization could lead to a shorter distance for the regenerating axons …