Neuroprotective Agents in Glaucoma

Abstract

1.1 Glaucoma as a neurodegenerative disorder Glaucoma is a multifactorial disease in which multiple genetic, systemic and environmental factors interact to precipitate the disease. Increased intraocular pressure (IOP) is believed to be one of the major factors responsible for glaucomatous cell death. (Guo et al., 2005). The axons of the optic nerve make a twisting exit through the fenestrated collageneous barrier (the lamina cribrosa) before entering the brain. It has been proposed that increased IOP causes mechanical stress to the lamina cribrosa, which in turn exerts pressure on the axons that pass through it. This pressure may block the passage of essential material through the axons; which would lead to a slow degeneration of the axons of the retinal ganglion cells (RGCs) (Howell et al., 2007). With increased IOP, gradual withdrawal of trophic factor from RGCs has been observed in a mouse model. Also apoptosis was observed to be a significantly delayed in RGCs in such conditions (Johnson et al., 2000). It was therefore proposed that with increased IOP and mechanical stress on the lamina cribrosa, axons of RGCs are lost much earlier than the cell body of the RGCs. Thus RGCs become ineffective in their visual function much earlier than actual phenotypic changes are observed in the retina/optic disc, as they are incapable of sending visual signals to the visual center of the brain (Whitmore et al., 2005). The primary goal of glaucoma treatment is to preserve vision. Elevated IOP as an important risk factor for glaucoma has continued to be a clinical focus for several reasons, including limited knowledge of the factors causing optic nerve damage, ease of measurement, the number of available IOP-reducing therapies, and the relationship of elevated IOP to disease progression. However, the relationship between IOP reduction and glaucoma damage is less clear, and such ambiguities suggest that factors other than IOP may be responsible for some of the long-term damage from glaucoma. Ocular blood flow in various tissues (e.g. retina, iris, optic nerve and choroid) was found to be reduced in glaucoma patients (Flammer et al., 2002). The blood flow reduction was more pronounced in Normal Tension Glaucoma (NTG) patients (Mozaffarieh et al., 2008). Interestingly, reduction of blood flow was also observed in the nailbed capillaries of fingers in glaucoma patients; suggesting that global vascular dysregulation is involved in Primary Open Angle Glaucoma (POAG) especially in NTG cases. Glaucoma is therefore no longer diagnosed by elevated IOP levels, and is now recognized as a neuropathy defined by characteristic optic disc and visual field change (Walland et al., 2006). IOP level is no longer relied on as a diagnostic criterion because 20% to 30% of glaucoma patients have IOP in the normal range (typically 10-21 mm Hg) (Sommer et al., 1991). Furthermore, there is annual progression even in patients treated with IOP-lowering