2-chloro-n(6)-(3-iodobenzyl)adenosine-5--n-methyluronamide and Retinal-Degeneration

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 A

Topics: Adenosine; Adenosine A3 Receptor Agonists; Animals; Axonal Transport; Cell Death; Cell Survival; Female; Neuroprotection; Ocular Hypertension; Optic Nerve; Rats, Sprague-Dawley; Receptor, Adenosine A3; Retinal Degeneration; Retinal Ganglion Cells; Up-Regulation

Glaucoma is a progressive chronic retinal degenerative disease and a leading cause of global irreversible blindness, characterized by optic nerve damage and retinal ganglion cell (RGC) death. Elevated intraocular pressure (IOP) is a main risk factor of glaucoma. Neuroinflammation plays an important role in glaucoma. We have been demonstrating that elevated pressure triggers microglia reactivity that contribute to the loss of RGCs. Adenosine, acting on adenosine receptors, is a crucial modulator of microglia phenotype. Microglia express all adenosine receptors. Previously, we demonstrated that the activation of adenosine A

Topics: Adenosine; Adenosine A3 Receptor Agonists; Animals; Cell Death; Cell Movement; Cell Proliferation; Glaucoma; Humans; Intraocular Pressure; Microglia; Optic Nerve; Optic Nerve Injuries; Phagocytosis; Rats; Receptor, Adenosine A3; Retinal Degeneration; Retinal Ganglion Cells

Death of retinal neural cells, namely retinal ganglion cells (RGCs), is a characteristic of several retinal neurodegenerative diseases. Although the role of adenosine A3 receptor (A3R) in neuroprotection is controversial, A3R activation has been reported to afford protection against several brain insults, with few studies in the retina. In vitro models (retinal neural and organotypic cultures) and animal models [ischemia-reperfusion (I-R) and partial optic nerve transection (pONT)] were used to study the neuroprotective properties of A3R activation against retinal neurodegeneration. The A3R selective agonist (2-Cl-IB-MECA, 1 μM) prevented apoptosis (TUNEL(+)-cells) induced by kainate and cyclothiazide (KA + CTZ) in retinal neural cultures (86.5 ± 7.4 and 37.2 ± 6.1 TUNEL(+)-cells/field, in KA + CTZ and KA + CTZ + 2-Cl-IB-MECA, respectively). In retinal organotypic cultures, 2-Cl-IB-MECA attenuated NMDA-induced cell death, assessed by TUNEL (17.3 ± 2.3 and 8.3 ± 1.2 TUNEL(+)-cells/mm(2) in NMDA and NMDA+2-Cl-IB-MECA, respectively) and PI incorporation (ratio DIV4/DIV2 3.3 ± 0.3 and 1.3 ± 0.1 in NMDA and NMDA+2-Cl-IB-MECA, respectively) assays. Intravitreal 2-Cl-IB-MECA administration afforded protection against I-R injury decreasing the number of TUNEL(+) cells by 72%, and increased RGC survival by 57%. Also, intravitreal administration of 2-Cl-IB-MECA inhibited apoptosis (from 449.4 ± 37.8 to 207.6 ± 48.9 annexin-V(+)-cells) and RGC loss (from 1.2 ± 0.6 to 8.1 ± 1.7 cells/mm) induced by pONT. This study demonstrates that 2-Cl-IB-MECA is neuroprotective to the retina, both in vitro and in vivo. Activation of A3R may have great potential in the management of retinal neurodegenerative diseases characterized by RGC death, as glaucoma and diabetic retinopathy, and ischemic diseases.

Topics: Adenosine; Adenosine A3 Receptor Agonists; Adenosine A3 Receptor Antagonists; Animals; Animals, Newborn; Apoptosis; Cell Survival; Disease Models, Animal; Excitatory Amino Acid Agonists; Fluorescent Antibody Technique, Indirect; In Situ Nick-End Labeling; Intravitreal Injections; Male; N-Methylaspartate; Neuroprotection; Optic Nerve Injuries; Organ Culture Techniques; Rats; Rats, Wistar; Receptor, Adenosine A3; Retina; Retinal Degeneration; Retinal Neurons