**1. Introduction**

Glaucoma has long been considered an irreversible progressive optic neuropathy with associated visual loss. Elevated intraocular pressure (IOP) was once considered the main modifiable risk for progression of glaucoma and has been the target for treatment. The pathogenesis of glaucoma was originally based on the mechanical and vascular dysregulation theory, however, this has evolved over the past decade. With the classification of low tension glaucoma, it is now recognized that the damage that occurs in the optic disc is not directly due to the elevated IOP and may be independent of this risk factor. Even though clinicians may aim for a target pressure, progression of optic disc cupping and visual field loss can still continue despite normal IOPs.

In contemplating a systematic approach to neuroprotection, the main areas to target include 1) neurotoxic agents such as nitric oxide and glutamate, 2) deprivation of internal neurotrophic factors 3) balancing self-repair with self-destruction in ocular nerve tissue and, 4) ocular blood flow and combating ischemia [1,2,3]. Focus in this chapter is dedicated to reviewing the mechanisms involved in the pathophysiology of neurodegeneration, target processes that offer neuroprotection, and the chemical and genetic interventions bearing potential for increasing retinal ganglion cell (RGC) survival. Glaucoma has cellular and molecular neurodegenerative pathways akin to those of other neurodegenerative disorders such as alzheimer's and parkin‐ sons, which increases the accessibility to possible treatment options.

Gene therapy targets increased conventional and uveoscleral outflow, reduced aqueous production and prevention of wound healing in addition to neuroprotection. Interfering with the apoptosis cycle by gene therapy has also being considered by increasing neurotrophic factors [4]. Intravitreal injections of brain-derived neurotrophic factor (BDNF), a neurotrophin that improves neurogenesis and survival are being studied. Interestingly it has recently been noted in animal models that short periods of hyperglycemia may be protective to the retinal ganglion cells during periods of elevated intra ocular pressure [5].

© 2013 Mowatt and Intosh; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Neuroprotection is the strategy to prevent retinal ganglion cell death. There have been several methods, many still experimental, aimed at reducing glutamate excitotoxicity, nitric oxide, free radical production and tumour necrosis factor (TNF) inhibition [1-4,6]. With the latest research, glaucoma, which was once thought to be an optic neuropathy, then a retinal disease, is now being considered a neurodegenerative disease, like alzheimer and parkinson [7].

vation of neurotrophic factors. It is also theorized that a secondary release or decreased uptake of glutamate via the müller cells is another cause for retinal ganglion cell apoptosis. It has been noted that retinal ganglion cell death has been associated with elevated IOP with positive correlation with an increase in matrix metallopetidase- 9 (MMP-9) activity (P<0.001), tissue

Strategies for Neuroprotection in Glaucoma http://dx.doi.org/10.5772/53776 205

With increased IOP, structural changes occur in the optic nerve head. There are several proposed theories for this effect. The mechanical bowing of the lamina cribrosa and loss of the axons may occur because of the hypo perfusion secondary to increased IOP. Optic nerve damage may be more prominent in hypotensive patients which may in part be due reduced perfusion and resulting oxidative stress from the induced hypoxia associated with reduced blood flow. In addition to this elevated IOP results in remodelling of the lamina cribrosa which may be a result of an increased synthesis of extracellular matrix ; matrix metalloproteases

The upregulation of MMP may be due to either the vascular insufficiency with resulting ischemia or secondary to increased endothelin and TNF α production [12]. There is a significant correlation between MMP-9 activity and both RGC apoptosis (P <0.001) and loss of laminin (P <0.01) [8,9]. This change in the structure of the lamina cribosa may result in damage to the retinal ganglion cell axons as they traverse it [13]. Astrocyte activation can result from ischemia, increased hydrostatic pressure or damaged axons and this can propagate the process of structurally changing the lamina cribrosa, resulting in further damage to the transversing

Glutamate is an excitatory neurotransmitter that is continuously released by photoreceptors and OFF bipolar cells in the dark which results in the dark current. Light stimuli starts the process of phototransduction which leads to reduced glutamate concentration in the synaptic cleft. Glutamate transporters allow for the uptake of glutamate by müller cells which is converted by glutamine synthetase into glutamine which is then released by the glial cells. This glutamine is taken up by the neurons and hydrolysed by glutaminase to glutamate again. Glutamate allows the influx of calcium, resulting in high intracellular calcium levels which promote apoptosis. Glutamate in excess is neurotoxic, due to its induced excitotoxicity. The glutamate-glutamine

cycle allows for natural homeostasis between the neurons and the glial cells (Figure 1).

Glutamate is released from degenerating cells or reduced uptake from müller's cells can increase the presence of glutamate. RGC may undergo apoptosis directly because of increased glutamate excitotoxicity. Müller cells can be injured by the excess glutamate which results in

Glutamate ionotropic receptors are found on the post synaptic bipolar, horizontal, amacrine and ganglion cells. They are gating cation channels that are classified into 3 groups; N-methyl-D-aspartate (NMDA) receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

inhibitor of matrix metalloproteinase (TIMP-1) (P<0.05) and collagen 1 (P<0.01) [8].

(MMP), collagen I and IV and elastin [9-11].

ganglion cell axons [14,15].

a secondary RGC death [16].

**4. Glutamate**

This chapter will review the present pathophysiology theories of neurodegeneration in glaucoma and highlight the latest updates in neuroprotection strategies, mechanisms that block apoptosis and improving the survival and functionality of the retinal ganglion cell.
