br Acknowledgements Dr Paul J Gasser is supported by

Acknowledgements Dr. Paul J. Gasser is supported by the National Institutes of Health (grant number R01DA032895), and the Charles E. Kubly Mental Health Research Center. Dr. Christopher A. Lowry is supported by the National Institutes of Health (grant number R21 MH116263), the Department of the Navy, Office of Naval Research Multidisciplinary University Research Initiative (MURI) Award (grant number N00014-15-1-2809), Department of Veterans Affairs Office of Research and Development (VA-ORD) RR&D Small Projects in Rehabilitation Research (SPiRE) (I21) (grant number 1 I21 RX002232-01), the Colorado Clinical and Translational Sciences Institute (CCTSI) Center for Neuroscience (grant number CNSTT-15-145), the Colorado Department of Public Health and Environment (CDPHE; grant number DCEED-3510), and the Alfred P. Sloan Foundation (grant number G-2016-7077). Christopher A. Lowry serves on the Scientific Advisory Board of Immodulon Therapeutics Ltd.
Introduction Glaucoma remains the main reason of irreversible visual loss worldwide (Almasieh et al., 2012). While glaucoma is characterized by the death of retinal ganglion Nicotine (RGCs), the mechanism causing that remains unclear (Almasieh et al., 2012). Excitotoxicity, glutamate-induced toxic effects to RGCs, is one of several mechanisms of RGC loss suggested in glaucoma. Growing evidence suggests that attenuation of NMDA receptor reactivity with the NMDA blocker protects RGCs in rat (Dong et al., 2008; Kim et al., 2007b; WoldeMussie et al., 2002), monkey (Hare et al., 2004), and mouse (Harada et al., 2007; Ju et al., 2009) glaucoma models (Aihara et al., 2014). Abundant NMDA glutamate receptors in the RGCs let them particularly susceptible to excessive glutamate (Brandstatter et al., 1994). We previously demonstrated that upregulation of NMDA receptors was involved in the pathogenesis of RGC loss in a chronic ocular hypertension rat model (Kim et al., 2007b). One of the important functions of Müller cells is the regulation of synaptic activity through preserving low concentration of glutamate via the excitatory amino acid transporter 1(EAAT1), glutamate/aspartate transporter [GLAST]) (Newman and Reichenbach, 1996). In EAAT1-knockout mice, the total retinal level of glutamate is increased, about two-fold, versus that in the wild-type (Sarthy et al., 2004) and progressive RGC loss occurs (Harada et al., 2007). For treatment of primary open angle glaucoma, intraocular pressure (IOP)-lowering treatment with topical medication is the first-line management in clinical practice (Bucolo et al., 2013; Quigley, 2011). Main classes of glaucoma eye drops include prostaglandin analogs, beta-blockers, carbonic anhydrase inhibitors, sympathomimetics and miotics (Bucolo et al., 2013). Among sympathomimetics, brimonidine is a selective α2-adrenoceptor agonist which is commonly used to decrease IOP in the treatment of glaucoma. The optic nerve crush rat model or the ischemic retinal injury model has demonstrated that α2 agonists have neuroprotective properties in optic nerve degeneration (Dai et al., 2013; Fujita et al., 2013; Lee et al., 2012). Systemic application of brimonidine provided neuroprotection to RGCs without having little effect on IOP also in chronic ocular hypertension model (Ahmed et al., 2001; Dong et al., 2008; Hernandez et al., 2008; WoldeMussie et al., 2001). The mechanism by which α2-adrenoceptor agonists improve ganglion cell survival remains unclear. Donello et al. demonstrated that activation of the α2-adrenergic receptor protected retinal structure and function from the effects of transient ischemia by preventing the accumulation of extracellular glutamate and aspartate (Donello et al., 2001). The molecular mechanism by which α2 agonists block ischemia-induced accumulation of glutamate may be related with NMDA receptors. Systemic treatment with brimonidine blocked the elevation of NMDA receptors expression in ischemic retina (Lee et al., 2012) and reduced RGC loss in rabbit retinal excitotoxicity models and rat glaucoma models by modulating NMDA receptor function (Dong et al., 2008).