OPTIC NERVE REGENERATION

 

The optic nerve is regarded as an extension of the brain. It is usually recognized that once damaged, the optic nerve does not regenerate, leading to visual loss lasting the lifetime of the individual. The degeneration of the optic nerve follows a timeline of events, starting milliseconds to hours after the initiating event, such as trauma or ischemia.

A few days after axonal injury, the associated retinal ganglion cells (RGCs) begin to degenerate. This is especially so if the injury is close to the eye.

The mature optic nerve contains many molecules that suppress axon growth, including the myelin-associated inhibitors Nogo-A, myelin-associated glycoprotein, and oligodendrocyte-myelin glycoprotein; proteoglycans that accumulate in the scar at the injury site; and additional axon repellants (eg, semaphorins).

The death of RGCs can be prevented almost completely by overexpression of the antiapoptotic Bcl family proteins, such as, Bcl-2 and Bcl-xL.

However, the regeneration and survival of axons is also dependent on numerous intracellular signaling pathways. This is seen when RGCs overexpressing Bcl-2 or Bcl-xL fail to regenerate axons, unless provided with additional growth factors.

A number of trophic factors can slow, but not completely stop, the death of RGCs. These factors include ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), neurotrophin 4/5 nerve growth factor, Fibroblast growth factor-2 (FGF-2), insulin-like growth factor-1, granulocyte colony-stimulating factor, glial-derived neurotrophic factor, and neurturin. 

The death of axotomized RGCs is also slowed by preventing caspase cleavage, blocking the nuclear enzyme poly (adenosine diphosphate–ribose) polymerase (a substrate for caspases), blocking nitric oxide synthase, introducing reducing agents, or inhibiting cell death via caspase-independent pathways. Long-term prevention of RGC death after axotomy may require the development of long-term delivery systems or a combination of treatments.

Two molecules present in the eye were found to stimulate mature RGCs to regenerate their axons. One is mannose, a simple sugar that is abundant in the vitreous. Mannose stimulates RGCs to extend moderately long axons if cells have sufficiently high levels of intracellular cyclic adenosine monophosphate (cAMP). The second growth factor is oncomodulin (Ocm), a 12-kDa, calcium-binding protein secreted by macrophages. 

The death of axotomized RGCs can be slowed by preventing caspase cleavage, blocking the nuclear enzyme poly(adenosine diphosphate–ribose) polymerase (a substrate for caspases), blocking nitric oxide synthase, introducing reducing agents, or inhibiting cell death via caspase-independent pathways. 

The advances during the past few years give hope for the possibility that at least some RGCs will be able to regenerate their axons all the way to their central targets. The future challenges will include finding ways to optimize this regeneration and testing whether they restore functionally meaningful levels of vision.

REFERENCES:

Li HJ, Sun ZL, Yang XT, Zhu L, Feng DF. Exploring Optic Nerve Axon Regeneration. Curr Neuropharmacol. 2017;15(6):861-873.

Benowitz LI, Yin Y. Optic Nerve Regeneration. Arch Ophthalmol. 2010;128(8):1059–1064. doi:10.1001/archophthalmol.2010.152.