Adenosine, adenosine receptors and glaucoma: An updated overview

Abstract

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 A₁ AR can reduce outflow resistance and thereby lower IOP, A₃ receptor antagonists prevent adenosine-induced activation of Cl⁻ channels of the ciliary non-pigmented epithelial cells and thereby lower IOP. A₁ and A_2A agonists can reduce vascular resistance and increase retina and optic nerve head blood flow. A₁ agonist and A_2A antagonist can enhance the recovery of retinal function after ischemia attack. Adenosine acting at A₃ receptors can attenuate the rise in calcium and retinal ganglion cells death accompanying P2X(7) receptor activation.

General significance

Evidence suggested that the adenosine system is one of the potential target systems for therapeutic approaches in glaucoma.

Introduction

Glaucoma, characterized by optic nerve head cupping and visual field defects, is a common cause of preventable and irreversible blindness worldwide [1], [2], [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 retinal 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 involve 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 prospective randomized multi-center studies have identified that IOP reduction with either medicines or surgery can reduce the development and progression of vision loss in glaucoma patients [8], [9], [10], [11], [12], [13], [14]. However, some cases have been shown to progress to blindness in spite of sufficient control of IOP [15], therefore, some IOP-independent mechanisms may also play an important role in glaucoma [16], [17], [18]. It is assumed that IOP-independent therapy may be a novel approach to treat glaucoma. One of the IOP-independent mechanisms is insufficient 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 management of glaucoma with ischemic events in addition to ocular hypotensive therapy [19].

IOP is generated in the anterior eye via the aqueous humor circulation system. Aqueous humor is produced by the ciliary body epithelium 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 evidence indicates that the conventional outflow pathway is the main site of homeostatic regulation of IOP [22], [24], [25], [26], [27], and the normal aqueous humor outflow resistance resides in the inner wall region of the trabecular meshwork outflow pathways [28], [29]. The site of highest resistance remains uncertain [21], [30], but likely resides at the confluence of the TM, JCT, and SC inner wall [21], [31]. In this small area, the TM consists of flat beams or plates of ground-substance, collagenous and elastin-like fibers covered by a complete layer of endothelial cells [32]. The JCT consists of a 5- to 10-μm-thick array of fibroblast-like cells intermingled and attached to each other, to the SC inner wall and to surrounding fine collagen and elastin-like fibrils [32]. The SC endothelial cells are connected by unusually leaky tight junctions [33], but aqueous humor likely crosses the inner wall through giant vacuoles associated with transendothelial pores [32], [34]. Two hypotheses have been proposed for elucidating the trabecular outflow resistance [35]. One hypothesis is based on the observation that eyes with glaucoma show a significant increase in banded fibrillar ECM in the juxtacanalicular region of the trabecular meshwork [36], [37], leading to the assumption that the elevation of outflow resistance is attributable to changes in the amount and quality of the ECM in this region [38], [39]. The ECM hypothesis is also supported by the observation that perfusion of anterior eye segments in organ cultures with metalloproteinases that digest ECM components leads to a reversible increase in outflow facility [40]. The other hypothesis is based on the discovery that the cells of the trabecular meshwork have contractile properties [41] and that an increase in trabecular meshwork tone increases outflow resistance [42]. Thereby, an increase in the contraction state of trabecular meshwork cells in glaucoma might lead to higher rigidity of the trabecular meshwork and to an increased outflow resistance. The contractility hypothesis is supported by the observation that experimental disruption of the actin cytoskeleton of the trabecular meshwork decreases outflow resistance [43], [44] and by recent findings which provide evidence that the trabecular meshwork of patients with primary open angle glaucoma (POAG) is stiffer than that of age-matched controls [45]. The two hypotheses are not mutually exclusive, since it is possible that trabecular meshwork cells that increase their contractile capabilities simultaneously synthesize more fibrillar matrix to transmit more force.

Research efforts through the last two decades have shed light on the important roles of adenosine and adenosine receptors (ARs) on aqueous humor formation, outflow facility, IOP, ocular blood flow and optic nerve protection, etc. The purpose of this review is to summarize the roles of adenosine and ARs in IOP modulation and neuroprotection in the disease of glaucoma.