Neuroregeneration

Source: Wikipedia, the free encyclopedia.
Not to be confused with Neurogenesis.

Neuroregeneration involves the regrowth or repair of

chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glial foot processes invade the dead synapse.[1]

Spinal cord injuries alone affect an estimated 10,000 people each year.[3] As a result of this high incidence of neurological injuries, nerve regeneration and repair, a subfield of neural tissue engineering
, is becoming a rapidly growing field dedicated to the discovery of new ways to recover nerve functionality after injury.

The nervous system is divided by neurologists into two parts: the

ganglia). While the peripheral nervous system has an intrinsic ability for repair and regeneration, the central nervous system is, for the most part, incapable of self-repair and regeneration. There is currently no treatment for recovering human nerve-function after injury to the central nervous system.[4] Multiple attempts at nerve re-growth across the PNS-CNS transition have not been successful.[4] There is simply not enough knowledge about regeneration in the central nervous system. 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. Neuroregeneration is important clinically, as it is part of the pathogenesis of many diseases, including multiple sclerosis
.

Peripheral nervous system regeneration

Main article:
Peripheral nerve injury
Guillain–Barré syndrome – nerve damage

Neuroregeneration in the peripheral nervous system (PNS) occurs to a significant degree.

cell body is intact, and they have made contact with the Schwann cells in the endoneurium (also known as the endoneurial tube or channel). Human axon growth rates can reach 2 mm/day in small nerves and 5 mm/day in large nerves.[4] The distal segment, however, experiences Wallerian degeneration within hours of the injury; the axons and myelin degenerate, but the endoneurium remains. In the later stages of regeneration the remaining endoneurial tube directs axon growth back to the correct targets. During Wallerian degeneration, Schwann cells grow in ordered columns along the endoneurial tube, creating a band of Büngner cells that protects and preserves the endoneurial channel. Also, macrophages and Schwann cells release neurotrophic factors
that enhance re-growth.

Central nervous system regeneration

Unlike peripheral nervous system injury, injury to the central nervous system is not followed by extensive regeneration. It is limited by the inhibitory influences of the glial and

Growth factors are not expressed or re-expressed; for instance, the extracellular matrix is lacking laminins. Glial scars rapidly form, and the glia actually produce factors that inhibit remyelination and axon repair; for instance, NOGO and NI-35.[6][7][8] The axons themselves also lose the potential for growth with age, due to a decrease in GAP43
expression, among others.

Slower degeneration of the distal segment than that which occurs in the peripheral nervous system also contributes to the inhibitory environment because inhibitory myelin and axonal debris are not cleared away as quickly. All these factors contribute to the formation of what is known as a

Llinás' law).[10]

Inhibition of axonal regrowth

Further information: Glial scar

Glial cell scar formation is induced following damage to the nervous system. In the central nervous system, this glial scar formation significantly inhibits nerve regeneration, which leads to a loss of function. Several families of molecules are released that promote and drive glial scar formation. 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.[11]
The up-regulated molecules alter the composition of the extracellular matrix in a way that has been shown to inhibit neurite outgrowth extension. This scar formation involves several cell types and families of molecules.

Chondroitin sulfate proteoglycan

In response to scar-inducing factors,

RhoA
pathway is involved. 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.

Keratan sulfate proteoglycans

Like the chondroitin sulfate proteoglycans, keratan sulfate proteoglycan (KSPG) production is up regulated in reactive astrocytes as part of glial scar formation. KSPGs have also been shown to inhibit neurite outgrowth extension, limiting nerve regeneration. Keratan sulfate, also called keratosulfate, is formed from repeating disaccharide galactose units and N-acetylglucosamines. It is also 6-sulfated. This sulfation is crucial to the elongation of the keratan sulfate chain. A study was done using N-acetylglucosamine 6-O-sulfotransferase-1 deficient mice. The wild type mouse showed a significant up regulation of mRNA expressing N-acetylglucosamine 6-O-sulfotransferase-1 at the site of cortical injury. However, in the N-acetylglucosamine 6-O-sulfotransferase-1 deficient mice, the expression of keratan sulfate was significantly decreased when compared to the wild type mice. 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.[11]

Other inhibitory factors

Proteins of oligodendritic or glial debris origin that influence neuroregeneration:

Clinical treatments

Neurons replacement

in vivo glias to neurons reprogramming

Transcription factors, activation of genes (using CRISPR activation[16]) or small molecules are used to reprogram glias into neurons.

The most commonly targeted glias are astrocytes (usually using GFAP) because they share the same lineage as neurons and region—specific transcription signatures,[16] while the vector used is typically an adeno-associated virus because some serotypes pass the blood brain barrier and it does not cause disease.

Targeted genes usually depend on the type of neuron sought; (NGN2 is known to produce glutamatergic, ASCL1: GABAergic...); RBPJ-k blocks the Notch pathway and elicits a neurogenic program[17] and Sox2 can also increase reprograming efficiency by causing a dedifferentiation and self-amplification phase before maturating as neurons.

While theses techniques show lot of promise in animal models for many otherwise incurable

brain injuries, no clinical trials
have started as of 2023.

Neural stem cells grafting

Tissue regrowth

Peripheral

Surgery

Surgery can be done in case a peripheral nerve has become cut or otherwise divided. This is called

surgical tourniquet is almost always used.[18]

Prognosis

The expectations after surgical repair of a divided peripheral nerve depends on several factors:

Autologous nerve grafting

Currently, autologous nerve grafting, or a nerve autograft, is known as the gold standard for clinical treatments used to repair large lesion gaps in the peripheral nervous system. It is important that nerves are not repaired under tension,[18] which could otherwise happen if cut ends are reapproximated across a gap. 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. However, this is not a perfect treatment; often the outcome is only limited function recovery. Also, partial de-innervation is frequently experienced at the donor site, and multiple surgeries are required to harvest the tissue and implant it.

When appropriate, a nearby donor may be used to supply innervation to lesioned nerves. Trauma to the donor can be minimized by utilizing a technique known as end-to-side repair. In this procedure, an epineurial window is created in the donor nerve and the proximal stump of the lesioned nerve is sutured over the window. Regenerating axons are redirected into the stump. Efficacy of this technique is partially dependent upon the degree of partial neurectomy performed on the donor, with increasing degrees of neurectomy giving rise to increasing axon regeneration within the lesioned nerve, but with the consequence of increasing deficit to the donor.[19]

Some evidence suggests that local delivery of soluble neurotrophic factors at the site of autologous nerve grafting may enhance axon regeneration within the graft and help expedite functional recovery of a paralyzed target.[20][21] Other evidence suggests that gene-therapy induced expression of neurotrophic factors within the target muscle itself can also help enhance axon regeneration.[22][23] 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.

Allografts and xenografts

Variations on the nerve autograft include the

xenograft
. In allografts, the tissue for the graft is taken from another person, the donor, and implanted in the recipient. Xenografts involve taking donor tissue from another species. Allografts and xenografts have the same disadvantages as autografts, but in addition, tissue rejection from immune responses must also be taken into account. Often immunosuppression is required with these grafts. Disease transmission also becomes a factor when introducing tissue from another person or animal. Overall, allografts and xenografts do not match the quality of outcomes seen with autografts, but they are necessary when there is a lack of autologous nerve tissue.

Nerve guidance conduit

Because of the limited functionality received from autografts, the current gold standard for nerve regeneration and repair, recent

nerve guidance conduits in order to guide axonal regrowth. The creation of artificial nerve conduits is also known as entubulation because the nerve ends and intervening gap are enclosed within a tube composed of biological or synthetic materials.[24]

Immunisation

A direction of research is towards the use of drugs that target remyelinating inhibitor proteins, or other inhibitors. Possible strategies include vaccination against these proteins (active immunisation), or treatment with previously created antibodies (

passive immunisation). These strategies appear promising on animal models with experimental autoimmune encephalomyelitis (EAE), a model of MS.[25]
Monoclonal antibodies have also been used against inhibitory factors such as NI-35 and NOGO.[26]

See also

References

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Further reading

Gobrecht P, Andreadaki A, Diekmann H, Heskamp A, Leibinger M, Fischer D (April 2016). "Promotion of Functional Nerve Regeneration by Inhibition of Microtubule Detyrosination". The Journal of Neuroscience. 36 (14): 3890–902.

PMID 27053198
.

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