The nervous system can be damaged in situations such as nerve damage or brain trauma. Neuroregeneration is only successful in peripheral nervous system (PNS) but not central nervous system (CNS) injuries.

PNS repair

The PNS is often damaged when nerves are cut or crushed (e.g. limb injuries). The recovery process is as follows:

1. The axon distal to the damage (and associated myelin) degenerates in a process known as Wallerian degeneration, leaving only the endoneurium (connective tissue around myelin sheath of each nerve fibre)
2. Schwann cells recruit macrophages and both phagocytose all debris
3. Cell body survives and re-induces axonal growth
4. Schwann cells promote regeneration and align in endoneurial tubes (forming Büngner bands) that guide regenerating fibres
5. Axons can regenerate at ~1 mm a day. However, if gap to endoneurial tube is too large (> 1 cm), regeneration may fail and axon end becomes a local swelling (neuroma) which may form intractable pain.

CNS damage

Types of CNS damage include loss of neurons and failed axon regeneration.

Loss of neurons

Due to the lack of stem cells in the nervous system, neuronal loss is irreplaceable. Other intact neuronal circuits may compensate. Loss of neurons may result from:

• Ischaemic injury (stroke)
• Neurodegeneration (e.g. Alzheimer’s disease, multiple sclerosis)

Possible treatment strategies include:

• Neural grafting: Grafting foetal neurons has seen some success in replacing dopamine neurons in substantia nigra for Parkinson’s. Complicated by ethical and logistical problems, side effects (e.g. dyskinesia) and cell death
• Stem cells: Stem (and progenitor) cells are able differentiate into and replace lost neurons. They exist in regions of the fetal brain (e.g. ventricular zone) and rare locations in the adult brain (e.g. hippocampus). Induced pluripotent stem cells can also be made from differentiated cells. Direct conversion can also produce induced neurons (and glia) from already differentiated cell types. However, there is no evidence yet that stem cells can produce functional benefits.

Axon regeneration faliure

Like in the PNS, Wallerian degeneration occurs distal to the lesion in a CNS axon. However, the proximal stump of the axon does not really regenerate more than 1mm (Cajal’s harsh decree). Likely due to the delicate nature of brain wiring, the CNS environment is non-permissive for axon growth. This includes:

• Lack of growth molecules (e.g. laminin)
• Oligodendrocytes secrete axon growth inhibitory proteins (e.g. Nogo-A)
• Astrocytes proliferate and produce growth-inhibitory CSPG (condroitin sulphate proteoglycans) in brain ECM. Astrocytes also form a dense scar that blocks axons.
• Perineuronal nets, specialised ECM that surround cell bodies and extend along dendrites (with holes at synapses) to stabilise established connections, are composed of a matrix of CSPGs.

Possible treatment strategies include:

• Provision of neurotrophic factors to promote growth
• Block anti-growth molecules (e.g. Nogo-A antibodies, CSPG degrading condroitinase
• Provide favourable surfaces for axon growth across lesion (e.g. olfactory ensheathing cells)
• Neural progenitor cell grafts at lesion to support axon regeneration or establish relays across lesion
• Epidural electrical stimulation of spinal cord with intense rehabilitation
• Promote circuit reorganisation (e.g. anti-Nogo-A immunotherapy to boost axon sprouting with intense rehabilitation to stabilise new circuits after stroke; reducing excitability at injured spinal cord to activate dormant connections)