Neuroregeneration
In addition, although the peripheral nervous system has the capability for regeneration, much research still needs to be done to optimize the environment for maximum regrowth potential.
[5][6] After an injury to the axon, peripheral neurons activate a variety of signaling pathways which turn on pro-growth genes, leading to reformation of a functional growth cone and regeneration.
Injury to the peripheral nervous system immediately elicits the migration of phagocytes, Schwann cells, and macrophages to the lesion site in order to clear away debris such as damaged tissue which is inhibitory to regeneration.
After injury, the proximal end swells and experiences some retrograde degeneration, but once the debris is cleared, it begins to sprout axons and the presence of growth cones can be detected.
Glial scars rapidly form, and the glia actually produce factors that inhibit remyelination and axon repair; for instance, NOGO and NI-35.
The most commonly targeted glias are astrocytes (usually using GFAP) because they share the same lineage as neurons and region—specific transcription signatures,[11] while the vector used is typically an adeno-associated virus because some serotypes pass the blood brain barrier and it does not cause disease.
While theses techniques show lot of promise in animal models for many otherwise incurable neurodegenerative diseases and brain injuries, no clinical trials have started as of 2023.
Nerve segments are taken from another part of the body (the donor site) and inserted into the lesion to provide endoneurial tubes for axonal regeneration across the gap.
Also, partial de-innervation is frequently experienced at the donor site, and multiple surgeries are required to harvest the tissue and implant it.
[15][16] Other evidence suggests that gene-therapy induced expression of neurotrophic factors within the target muscle itself can also help enhance axon regeneration.
[17][18] Accelerating neuroregeneration and the reinnervation of a denervated target is critically important in order to reduce the possibility of permanent paralysis due to muscular atrophy.
In the central nervous system, this glial scar formation significantly inhibits nerve regeneration, which leads to a loss of function.
For instance, transforming growth factors B-1 and -2, interleukins, and cytokines play a role in the initiation of scar formation.
The accumulation of reactive astrocytes at the site of injury and the up regulation of molecules that are inhibitory for neurite outgrowth contribute to the failure of neuroregeneration.
[22] The up-regulated molecules alter the composition of the extracellular matrix in a way that has been shown to inhibit neurite outgrowth extension.
Chondroitin sulfate proteoglycans (CSPGs) have been shown to be up regulated in the central nervous system (CNS) following injury.
Repeating disaccharides of glucuronic acid and galactosamine, glycosaminoglycans (CS-GAGs), are covalently coupled to the protein core CSPGs.
CSPGs have been shown to inhibit regeneration in vitro and in vivo, but the role that the CSPG core protein vs. CS-GAGs had not been studied until recently.
The wild type mouse showed a significant up regulation of mRNA expressing N-acetylglucosamine 6-O-sulfotransferase-1 at the site of cortical injury.
Similarly, glial scar formation was significantly reduced in the N-acetylglucosamine 6-O-sulfotransferase-1 mice, and as a result, nerve regeneration was less inhibited.
[22] Proteins of oligodendritic or glial debris origin that influence neuroregeneration: Gobrecht P, Andreadaki A, Diekmann H, Heskamp A, Leibinger M, Fischer D (April 2016).
