Neural Mechanisms Underlying Brimonidine’s Protection of Retinal Ganglion Cells in Experimental Glaucoma

Abstract

Glaucoma is a neurodegenerative disease characterized by a progressive loss of retinal ganglion cells (RGCs), the output neurons of the retina. Elevated intraocular pressure (IOP) has long been recognized as a major risk factor for human glaucoma (Kass et al., 1980; Quigley et al., 1994; Tsai & Kanner, 2005). Indeed, in animal models of glaucoma, ranging from rodents (Johnson & Tomarev, 2010) to primates (Gaasterland & Kupfer, 1974; Hare et al., 2004), elevated IOP produced either biophysically (Gaasterland & Kupfer, 1974; WoldeMussie et al., 2001) or genetically (Anderson et al., 2001; Ju et al., 2009) can lead to RGC degeneration similar to that found in human glaucoma (Quigley, 2005). A common and effective treatment for glaucoma is the use of IOP lowering topical drugs that act at a variety of cellular targets, such as the α2 and β adrenergic receptors (Tsai & Kanner, 2005). However, in many patients, the disease continues to progress despite successful IOP reduction with topical drugs (Heijl et al., 2002; Vasudevan et al., 2011). Brimonidine, a selective α2 receptor agonist, is the active ingredient in one class of topical IOP lowering drugs, such as Alphagan® and Alphagn-P®. Brimonidine has been shown to protect RGCs in experimental glaucoma (WoldeMussie et al., 2001; Dong et al., 2008), retinal ischemia (Donello et al., 2001; Lai et al., 2002), optic nerve injury (Yoles et a., 1999), and retinal excitotoxicity (Dong et al., 2008). In experimental glaucoma, brimonidine’s neuroprotective effect appears to be independent of its IOP lowering action (Dong et al., 2008; Hernandez et al., 2008). More recently, in a randomized, double-masked, multicenter clinical trial, brimonidine has been shown to be more effective in slowing disease progression (visual field loss), compared with timolol (a β blocker), despite the fact that the mean treated IOP was similar in both treatment groups at all time points (Krupin 2011). These clinical data suggest that brimonidine may have a direct RGC protective effect that is independent of its IOP lowering action in human low-pressure glaucoma, similar to that found in experimental glaucoma (Dong et al., 2008; Hernandez et al., 2008). In this chapter, we will summarize the results of our recent studies on the mechanisms that underlie brimonidine’s protection of RGCs in experimental glaucoma and retinal excitotoxicity. We will first describe the properties of RGCs and the ex vivo and in vivo models used in our studies on the mechanisms of RGC injury and protection. Then we will