The optic nerve is part of the CNS and represents a unidirectional neuronal path consisting of retinal ganglion cell axons that connect the eye with central visual areas. One of the marked features of the optic nerve, equally advantageous for clinicians and experimentalists is its extracranial location providing diagnostic and experimental accessibility. In addition to axons, oligodendrocytes myelinate the optic nerve, whereas astrocytes, microglial cells and a dense capillary network is pre sent throughout it length. Its microvasculature is assumed to be a major player in numerous optic nerve diseases such as glaucoma, microinfarctions, ischemias, embolisations, injuries, infections and hereditary diseases
Injury to the optic nerve results in irreversible destruction of the axons cumulating in bidirectional atrophy. Dissolution of the neuronal components results in gliotic scar formation and substantial remodeling of extracellular matrix that forms an environment which is forbidden for ingrowth and motility of new axons. Based on this inhibitory environment, retrograde signals to the ganglion cell bodies confer catabolic metabolism, thus initiating apoptotic cell death and gliotic responses within the retina, too. There is no method to replace death ganglion cells yet.
There are, however, increasing experimental lines of evidence delivered during the last decades that some of the ganglion cells can survive axotomy. They present encouraging findings that optic nerve repair may be possible at one time. The principal finding is that apoptosis can be prevented to some extent, and the catabolic responses of cells can be reversed towards a growth of axons. Ultimately, axons can grow as shown in a number of models including regrowth of axons within the inhospitable environment of the optic nerve. The approaches used are based on both neutralization of inhibitory substances at the site of axonal injury and neurotrophic/neuroprotective support at the ganglion cell bodies. On major impediment is the understanding of how acute axonal stump, as a prospective growth cone can be forced to become a motile growth cone. For this, first profound understanding of the molecular mechanisms determining interactions between growth cones and their micro-surround is essential. Then, knowledge of the panoply of molecular tools that are used for navigation through astrocytes, microglia oligodendrocytes and ECM is mandatory.
Next, the search for substances which increase the quantity of regenerating axons is necessary. Then, the mechanisms of signaling life or death is a fundamental requirement to apply such substances. Last not least, the question of reconnection of ganglion cell axons within the brain. Besides of acute injuries, similar aspects are applicable after chronic injuries and compressions like that of abnormal increase of intraocular pressure.
We have established in vitro and in vivo animal models of optic nerve regeneration and glaucoma. Together with our partners in proteomics and genomics we have been able to demonstrate that under certain circumstances ganglion cell axons can grow. We now begin to understand some of the signaling pathways of neuroprotection and created conditions for functional repair of the optic nerve.
Following aspects have been addressed in detail:
Institute of Experimental Ophthalmology
School of Medicine
48149 Münster, Germany