**3. Increased intraocular pressure**

Although neurodegeneration theories were considered because of progression despite normal IOPs, increased IOP does have a role in RGC death. Increased IOP can block axonal transport of the excitotoxic transmitter, glutamate, at the level of the lamina cribrosa, leading to depri‐ 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 inhibitor of matrix metalloproteinase (TIMP-1) (P<0.05) and collagen 1 (P<0.01) [8].

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

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 ganglion cell axons [14,15].
