Review Adenosine, adenosine receptors and glaucoma: An updated overview ☆ Yisheng Zhong a, b, ⁎, Zijian Yang a , Wei-Chieh Huang b , Xunda Luo b, ⁎⁎ a Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin No.2 Road, 200025, Shanghai, China b Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA abstract article info Article history: Received 19 November 2012 Received in revised form 21 December 2012 Accepted 7 January 2013 Available online 15 January 2013 Keywords: Adenosine Adenosine receptor Intraocular pressure Neuroprotection Glaucoma Background: Glaucoma, a leading cause of blindness worldwide, is an optic neuropathy commonly associated with elevated intraocular pressure (IOP). The major goals of glaucoma treatments are to lower IOP and protect retinal ganglion cells. It has been revealed recently that adenosine and adenosine receptors (ARs) have important roles in IOP modulation and neuroprotection. Scope of review: This article reviews recent studies on the important roles of adenosine and ARs in aqueous humor formation and outflow facility, IOP and retinal neuroprotection. Major conclusions: Adenosine and several adenosine derivatives increase and/or decrease IOP via A 2A AR. Activation of A 1 AR can reduce outflow resistance and thereby lower IOP, A 3 receptor antagonists prevent adenosine-induced activation of Cl - channels of the ciliary non-pigmented epithelial cells and thereby lower IOP. A 1 and A 2A agonists can reduce vascular resistance and increase retina and optic nerve head blood flow. A 1 agonist and A 2A antagonist can enhance the recovery of retinal function after ischemia attack. Adenosine acting at A 3 receptors can attenuate the rise in calcium and retinal ganglion cells death accom- panying P2X(7) receptor activation. General significance: Evidence suggested that the adenosine system is one of the potential target systems for therapeutic approaches in glaucoma. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Glaucoma, characterized by optic nerve head cupping and visual field defects, is a common cause of preventable and irreversible blind- ness worldwide [1–3]. Elevated intraocular pressure (IOP) is the most widely recognized risk factor for the onset and progression of glaucoma [4]. High IOP (above the tolerable range of the optic nerve) causes reti- nal ganglion cells (RGCs) axons degeneration at the optic nerve head in the region of the lamina cribrosa, a process that occurs in parallel to the apoptotic death of RGCs. The precise mechanisms that lead to the death of RGCs in glaucoma have not been fully identified, but might in- volve the blockade of both anterograde and retrograde axonal transport leading to the deprivation of neurotrophic signals [3]. Glaucomatous neuropathy might occur in parallel to a remodeling of the extracellular matrix (ECM) of the optic nerve head [3,5,6]. It is generally accepted that lowering IOP is a useful strategy to prevent and slow down the progression of glaucoma [7]. Several pro- spective randomized multi-center studies have identified that IOP re- duction with either medicines or surgery can reduce the development and progression of vision loss in glaucoma patients [8–14]. However, some cases have been shown to progress to blindness in spite of suf- ficient control of IOP [15], therefore, some IOP-independent mecha- nisms may also play an important role in glaucoma [16–18]. It is assumed that IOP-independent therapy may be a novel approach to treat glaucoma. One of the IOP-independent mechanisms is insuf- ficient blood supply to the optic nerve head and adjacent retina [19,20]. Therefore, it is likely that improving compromised ocular blood flow by vasodilation might be a useful strategy for the man- agement of glaucoma with ischemic events in addition to ocular hy- potensive therapy [19]. IOP is generated in the anterior eye via the aqueous humor circu- lation system. Aqueous humor is produced by the ciliary body epithe- lium and exits the anterior chamber by two main outflow pathways, trabecular (conventional) and uveoscleral (unconventional) (Fig. 1). The trabecular outflow pathway comprises the trabecular meshwork (TM), juxtacanalicular tissue (JCT), inner wall of Schlemm's canal (SC), collector channels, and aqueous veins in series [21], whereas the uveoscleral pathway consists of ciliary muscle and downstream choroid, sclera, and episcleral tissues [22,23]. IOP is maintained in equilibrium when the rate of aqueous production is equal to the rate of aqueous outflow. IOP elevation in glaucoma is associated with diminished or obstructed aqueous humor outflow. Much evi- dence indicates that the conventional outflow pathway is the main site of homeostatic regulation of IOP [22,24–27], and the normal aqueous humor outflow resistance resides in the inner wall region Biochimica et Biophysica Acta 1830 (2013) 2882–2890 ☆ Conflict of interest: None. ⁎ Correspondence to: Y. Zhong, Department of Ophthalmology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai 200025, P.R. China. ⁎⁎ Correspondence to: X. Luo, Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. E-mail addresses: yszhong68@yahoo.com.cn (Y. Zhong), luoxunda@mail.med.upenn.edu (X. Luo). 0304-4165/$ – see front matter © 2013 Elsevier B.V. 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