Targeting the A3 adenosine receptor for glaucoma treatment (Review)

Abstract

Abstract. Glaucoma is a worldwide disease and the second leading cause of blindness. Current treatments are associated with a number of side-effects and poor compliance, due to the requirement for treatment administration several times a day. These treatments typically aim to lower intraocular pressure (IOP); however, they are unable to protect retinal ganglion cells (RGCs) from undergoing apoptosis, which is the main cause of vision loss. A 3 adenosine receptor (A 3 AR) agonists have been found to protect normal cells from undergoing apoptosis via the downregulation of death signals. Furthermore, A 3 AR agonists have been reported to have several ophthalmological effects, including the prevention of ganglion cell apoptosis in vitro and in vivo and anti-inflammatory effects in experimental models of autoimmune uveitis. CF101, an orally bioavailable A 3 AR agonist, has been analyzed in dry eye syndrome phase II clinical trials and was identified to be safe and well tolerated. The anti-inflammatory effect of CF101 was shown to significantly improve corneal staining, tear meniscus and tear break-up time in dry eye patients. In addition, CF101 was found to decrease IOP in patients. The safety and efficacy of CF101, together with its suitability for oral administration, indicates that it has potential as a candidate drug for the treatment of glaucoma.

Structure-Activity Analysis of Biased Agonism at the Human Adenosine A3 Receptor

“…However, if similar bias profiles were observed within the cell type of interest, the discovery of biased cytoprotective compounds may have clinical implications when targeting the A 3 AR. A 3 AR activation is protective in cardiac and lung ischemiareperfusion injury and can prevent glaucoma-induced cell death (Matot et al, 2006;Headrick and Lasley, 2009;Fishman et al, 2013). Paradoxically, although low concentrations of A 3 AR agonists stimulate pro-survival signaling, high concentrations promote apoptosis (Jacobson, 1998).…”

The A3Adenosine Receptor: History and Perspectives

“…Interestingly, in the same clinical trial, CF101 decreased IOP, thus demonstrating its efficacy as an IOP-lowering agent. These data, and the anti-inflammatory characteristics of CF-101, support pursuing study of this drug as a potential treatment of the signs and symptoms of dry eye syndrome and glaucoma (Avni et al, 2010;Fishman et al, 2013). Indeed now CF101 has entered a phase II, randomized, double-masked, placebo-controlled, parallelgroup study of the safety and efficacy of daily CF101 administered orally in subjects with elevated intraocular pressure (ClinicalTrials.gov).…”

Ocular Cubosome Drug Delivery System for Timolol Maleate: Preparation, Characterization, Cytotoxicity, Ex Vivo, and In Vivo Evaluation

“…It is a chronic and progressive ophthalmic disease caused by the retinal ganglion cell apoptosis and subsequent gradual degeneration of neuronal tissue [2]. The major risk factor for the development of glaucoma is the increase in intraocular pressure (IOP) [3], which results in progressive loss of vision and irreversible blindness.…”