Neuroregeneration

Neuroregeneration refers to the regrowth or repair of the nervous system or its components tissues, cells or cell products. Such mechanisms may include remyelination, generation of new neurons, glia, axons, myelin or synapses. Neuroregeneration differs between the Peripheral Nervous System (PNS) and the Central Nervous System (CNS) by the functional mechanisms and especially, the extent and speed.

Neuroregeneration in the Peripheral Nervous System
Neuroregeneration in the PNS occurs to a significant degree.1

In the PNS, the myelin sheath surrounding axons is maintained and generated by Schwann cells.

Neuroregeneration in the Central Nervous System
The ability of the CNS to generate new neurons or to repair axons following trauma is very limited, especially when compared to the abilities of the PNS1. The environment within the CNS, especially following trauma, counteracts the repair of myelin and neurons. As growth factors are not expressed or re-expressed, glial scars rapidly form, and the glia and myelin actually produce factors that inhibit remyelination and axon repair.1,2,3,4

Neuroregeneration in Disease
Neurodegeneration is a symptom of Multiple Sclerosis, and following episodes of autoimmune attack on the nervous system, it is possible to have neuroregeneration occurring, which may result in repairing the damage dealt during the episode.

Neuroregenerative Therapies
A direction of research is towards the use of drugs that target remyelinating inhibitor proteins, or other inhibitors or neuroregeneration 3. 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.3

Proteins of Oligodendritic or Glial Debris Origin Responsible for Neuroregeneration

 * NOGO –The protein family Nogo, particularly Nogo-A, has been identified as an inhibitor of remyelination in the CNS, especially in autoimmune mediated demyelination, such as found in Experimental Autoimmune Encephalomyelitis (EAE) and Multiple Sclerosis (MS).1,3 Nogo A functions via either its amino-Nogo terminus through an unknown receptor, or by its Nogo-66 terminus through NgR1, p75, TROY or LINGO11. Antagonising this inhibitor results in improved remyelination,1,3 as it is involved in the RhoA pathway (see below).


 * MAG –Myelin Associated Glycoprotein acts via the receptors NgR2, GT1b, NgR1, p75, TROY and LINGO11.


 * OMgp –Oligodendrocyte Myelin glycoprotein


 * Ephrin B3 functions through the EphA4 receptor and inhibits remyelination.1


 * Sema 4D functions through the PlexinB1 receptor and inhibits remyelination.1

Proteins of Astrocytic Origin Responsible for Neuroregeneration

 * CSPGs- Chondroitin Sulfate ProteoGlycans act upon the RhoA pathways through an unknown receptor. Following trauma to the CNS, the astrocyte number around the trauma site rapidly increases, and thus the proteins expressed by the astrocytes, such as CSPGs concentrate.1

RhoA Pathway
Molecules act on various receptors, such as NgR1, LINGO1, p75, TROY and other unknown receptors (eg. by CSPGs), which stimulates RhoA. RhoA activates ROCK (RhoA kinase) which stimulates LIM kinase, which then stimulates Cofilin, which effectively re-organises the Actin cytoskeleton of the cell1. In the case of neurons, activation of this pathway results in growth cone collapse,1,3 therefore inhibits the growth and repair of neural pathways and axons. Inhibition of this pathway by its various components usually results in some level of improved remyelination.1,2,3,4