Axonal regeneration of retinal ganglion cells: effect of trophic factors

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Abstract

A variety of neurotrophic factors can influence the cell functions of the developing, mature and injured retinal ganglion cells. The discovery that retinal ganglion cell loss can be alleviated by neurotrophic factors has generated a great deal of interest in the therapeutic potential of these molecules. Recently, evidence has provided valuable information on the receptors that mediate these events and the intracellular signaling cascades after the binding of these ligands. Signaling by neurotrophic factors does not seem to restrict to retrograde messenger from the target but also includes local interactions with neighbouring cells along the axonal pathways, anterograde signaling from the afferents and autocrine signaling. More insight into the mechanisms of action of neurotrophic factors and the signal transduction pathway leading to the protection and regeneration of retinal ganglion cells may allow the design of new therapeutic strategies.

Section snippets

Response of retinal ganglion cells to axotomy

In mammals, retinal ganglion cells send axons to form the optic nerve. The axons from the temporal retina decussate at the optic chiasm whereas those from the nasal retina project to the ipsilateral part of the brain. The retinal fibers terminate in different visual nuclei responsible for various functions of the visual system. Damaging the axons of the retinal ganglion cells in the optic nerve or along its central pathways will result in a series of responses, which range from chromatolysis to

Intravitreal transplantation of peripheral nerve graft

Retinal ganglion cells in adult mammals do not regenerate their axons after damage. However, a peripheral nerve attached to the retina (So and Aguayo, 1985, So et al., 1986) or to the transected optic nerve (Berry et al., 1986, Politis and Spencer, 1986, Vidal-Sanz et al., 1987, Watanabe et al., 1991) will provide a good conduit for damaged retinal axons to regenerate. If a small segment of peripheral nerve is also transplanted into the vitreous, the number of regenerating retinal ganglion

Intravitreal transplantation of peripheral nerve sheath cells

It can be presumed that the non-neuronal cell constituents (Schwann cells and fibroblasts) are responsible for the promoting effect of a peripheral nerve graft on the survival and regeneration of retinal ganglion cells. Attempts to repair the damaged visual pathways may also include the promotion of survival of injured retinal ganglion cells by grafting with Schwann cells (Maffei et al., 1990). Due to the ability of Schwann cells to secrete neurotrophic factors, Schwann cells could enhance the

Endogenous sources of “retinotrophic” factors

The retinal ganglion cells, among the different cell types in the retina, have been studied extensively with regard to the effects of neurotrophic factors. Retinal ganglion cells which would normally die can be maintained in vitro if they are cultured with fragments of the superior colliculus, a major retinal target, or with conditioned medium or extracts prepared from the superior colliculus (Nurcombe and Bennett, 1981, Armson et al., 1987). It has been shown that retinal ganglion cells

Neurotrophic factors that promote the survival and regeneration of retinal ganglion cells

Some of the characterized neurotrophic factors have been demonstrated to provide trophic support for the retinal ganglion cells, despite the fact that several endogenous trophic agents described above have not been identified as any of the well-known neurotrophic factors. These factors may be of relevance for clinical application to promote the survival and axonal regeneration of the retinal ganglion cells. In this review, we will briefly describe some of the more important retinotrophic

Concluding remarks and future directions

The neurotrophic hypothesis is formulated on the basis that the survival of the developing neurons depends on the limited supply of neurotrophic factors in the target tissues. However, recent evidence dealing with neurotrophic factors has demonstrated the limitations of this basic concept. Neurons might derive trophic support not only from innervated cells, but also from afferent neurons, axon-ensheathing glial cells or themselves. Neurotrophic factors also interact less specifically than the

Acknowledgements

The research from the authors’ laboratories that is described herein was supported by research grants from the University of Hong Kong, the Research Grant Council of Hong Kong and from the Croucher Foundation of Hong Kong.

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