Adenosine A1 receptor: A neuroprotective target in light induced retinal degeneration

Abstract

Light induced retinal degeneration (LIRD) is a useful model that resembles human retinal degenerative diseases. The modulation of adenosine A1 receptor is neuroprotective in different models of retinal injury. The aim of this work was to evaluate the potential neuroprotective effect of the modulation of A1 receptor in LIRD. The eyes of rats intravitreally injected with N6-cyclopentyladenosine (CPA), an A1 agonist, which were later subjected to continuous illumination (CI) for 24 h, showed retinas with a lower number of apoptotic nuclei and a decrease of Glial Fibrillary Acidic Protein (GFAP) immunoreactive area than controls. Lower levels of activated Caspase 3 and GFAP were demonstrated by Western Blot (WB) in treated animals. Also a decrease of iNOS, TNFα and GFAP mRNA was demonstrated by RT-PCR. A decrease of Iba 1+/MHC-II+ reactive microglial cells was shown by immunohistochemistry. Electroretinograms (ERG) showed higher amplitudes of a-wave, b-wave and oscillatory potentials after CI compared to controls. Conversely, the eyes of rats intravitreally injected with dipropylcyclopentylxanthine (DPCPX), an A1 antagonist, and subjected to CI for 24 h, showed retinas with a higher number of apoptotic nuclei and an increase of GFAP immunoreactive area compared to controls. Also, higher levels of activated Caspase 3 and GFAP were demonstrated by Western Blot. The mRNA levels of iNOS, nNOS and inflammatory cytokines (IL-1β and TNFα) were not modified by DPCPX treatment. An increase of Iba 1+/MHC-II+ reactive microglial cells was shown by immunohistochemistry. ERG showed that the amplitudes of a-wave, b-wave, and oscillatory potentials after CI were similar to control values. A single pharmacological intervention prior illumination stress was able to swing retinal fate in opposite directions: CPA was neuroprotective, while DPCPX worsened retinal damage. In summary, A1 receptor agonism is a plausible neuroprotective strategy in LIRD.

CD73 controls ocular adenosine levels and protects retina from light-induced phototoxicity

“…Taking into account data on direct involvement of adenosinergic signaling in the modulation of light-evoked responses of retina [ 43 – 45 ], we hypothesized that pharmacological inhibition of the CD73–ADO axis may affect retinal function. Several novel CD73 inhibitors have been designed and synthesized recently in our laboratories based on N 6 -benzyl-α,β-methylene-ADP (PSB-12379) as a lead structure, which are characterized by exceptionally high selectivity, nanomolar inhibitory potency toward human, rat and mouse CD73, and high metabolic stability in human plasma and in rat liver microsomes [ 27 ].…”

Purinergic–Glycinergic Interaction in Neurodegenerative and Neuroinflammatory Disorders of the Retina

“…Gi protein-coupled A 1 adenosine receptor stimulation decreases and Gs protein-coupled A 2A receptors stimulation exerts an opposite effect on microglia activity (Table 2). The A 1 receptor agonist CPA inhibited TNFα and GFAP mRNA expression and the A 1 receptor antagonist DPCPX caused an opposite effect on GFAP immunoreactivity in the retina [54]. CPA also lowered TNFα mRNA expression in light-induced retinal degeneration in rats.…”

“…The A 1 receptor agonist CPA decreased the number of apoptotic nuclei and GFAP immunoreactivity in the retina exposed to excessive light to induce neurodegeneration. This effect was reversed by the A 1 receptor antagonist DPCPX [54].…”

ATP and Adenosine in the Retina and Retinal Diseases

“…These data suggest that the adenosine exerts an inhibitory influence on retinal neurons by modulating excitatory glutaminergic signaling, thus promoting retinal neural cells survival. Stimulation of A1R with the agonist N-Cyclopentiladenosine (CPA) protected against photoreceptor cell death in light-induced retinal degeneration model probably due to the presynaptic inhibition of glutamate release and the modulation of NMDA receptor activity ( Soliño et al, 2018 ). This protective capacity of adenosine at photoreceptor cell is consistent with neuromodulator role of adenosine in glutaminergic signaling.…”