Activation of adenosine A3 receptor protects retinal ganglion cells from degeneration induced by ocular hypertension

Abstract

Glaucoma is a progressive chronic retinal degenerative disease and a leading cause of global irreversible blindness. This disease is characterized by optic nerve damage and retinal ganglion cell (RGC) death. The current treatments available target the lowering of intraocular pressure (IOP), the main risk factor for disease onset and development. However, in some patients, vision loss progresses despite successful IOP control, indicating that new and effective treatments are needed, such as those targeting the neuroprotection of RGCs. Adenosine A3 receptor (A3R) activation confers protection to RGCs following an excitotoxic stimulus. In this work, we investigated whether the activation of A3R could also afford protection to RGCs in the laser-induced ocular hypertension (OHT) model, a well-characterized animal model of glaucoma. The intravitreal injection of 2-Cl-IB-MECA, a selective A3R agonist, abolished the alterations induced by OHT in the negative and positive components of scotopic threshold response (STR) without changing a- and b-wave amplitudes both in scotopic and photopic conditions. Moreover, the treatment of OHT eyes with the A3R agonist promoted the survival of RGCs, attenuated the impairment in retrograde axonal transport, and improved the structure of the optic nerve. Taking into consideration the beneficial effects afforded by 2-Cl-IB-MECA, we can envisage that A3R activation can be considered a good therapeutic strategy to protect RGCs from glaucomatous damage.

Activation of Adenosine A3 Receptor Inhibits Microglia Reactivity Elicited by Elevated Pressure

“…This is an in vitro study in which the contribution of other cells is not considered, but future studies evaluating whether A 3 R agonists can control microglia-mediated neuroinflammation in an animal model of ocular hypertension will help clarifying the potential anti-inflammatory effects of A 3 R activation. Taken these results showing that 2-Cl-IB-MECA reduces pro-inflammatory microglia responses elicited by elevated pressure and our previous reports [ 23 , 24 ], one may envisage that A 3 R activation may have protective properties to RGCs in glaucomatous conditions, not only by triggering survival mechanisms directly on A 3 R-expressing RGCs, but also by controlling microglia reactivity.…”

“…The A 3 R is expressed in RGCs [ 22 ] and the agonist 2-Cl-IB-MECA promotes neurite development in cultured RGCs and axon regeneration in an animal model of optic nerve crush [ 25 ]. Recently, we identified A 3 R as a molecular target with therapeutic potential to protect RGCs [ 23 ]. Moreover, we showed that the activation of the A 3 R is neuroprotective to retinal cells, including RGCs, from excitotoxic insults [ 24 ].…”

“…Moreover, we showed that the activation of the A 3 R is neuroprotective to retinal cells, including RGCs, from excitotoxic insults [ 24 ]. Furthermore, the intravitreal injection of 2-Cl-IB-MECA provides protection to RGCs against the damage induced by transient retinal ischemia, partial optic nerve transection and ocular hypertension [ 23 , 24 ].…”

“…The A 3 R has been described to be expressed in the retina [ 20 ], in retinal neural cell cultures [ 21 ], including RGCs [ 22 ]. Previously, we have described the protective properties of the A 3 R activation in the retina [ 23 ]. Indeed, the selective agonist of A 3 R, 2-Cl-IB-MECA prevents the death of retinal cells and affords protection to the retina [ 23 , 24 ].…”

“…Previously, we have described the protective properties of the A 3 R activation in the retina [ 23 ]. Indeed, the selective agonist of A 3 R, 2-Cl-IB-MECA prevents the death of retinal cells and affords protection to the retina [ 23 , 24 ]. Moreover, recently it was reported that A 3 R activation stimulates neurite development in RGC cultures and axonal regeneration in an animal model of optic nerve crush [ 25 ].…”