Retinal Toxicity Induced by Chemical Agents.

Vision is an important sense for humans, and visual impairment/blindness has a huge impact in daily life. The retina is a nervous tissue that is essential for visual processing since it possesses light sensors (photoreceptors) and performs a pre-processing of visual information. Thus, retinal cell dysfunction or degeneration affects visual ability and several general aspects of the day-to-day of a person's lives. The retina has a blood-retinal barrier, which protects the tissue from a wide range of molecules or microorganisms. However, several agents, coming from systemic pathways, reach the retina and influence its function and survival. Pesticides are still used worldwide for agriculture, contaminating food with substances that could reach the retina. Natural products have also been used for therapeutic purposes and are another group of substances that can get to the retina. Finally, a wide number of medicines administered for different diseases can also affect the retina. The present review aimed to gather recent information about the hazard of these products to the retina, which could be used to encourage the search for more healthy, suitable, or less risky agents.

Caffeine regulates GABA transport via A1R blockade and cAMP signaling.

Caffeine is the most consumed psychostimulant drug in the world, acting as a non-selective antagonist of adenosine receptors A1R and A2AR, which are widely expressed in retinal layers. We have previously shown that caffeine, when administered acutely, acts on A1R to potentiate the NMDA receptor-induced GABA release. Now we asked if long-term caffeine exposure also modifies GABA uptake in the avian retina and which mechanisms are involved in this process. Chicken embryos aged E11 were injected with a single dose of caffeine (30 mg/kg) in the air chamber. Retinas were dissected on E15 for ex vivo neurochemical assays. Our results showed that [3H]-GABA uptake was dependent on Na+ and blocked at 4 °C or by NO-711 and caffeine. This decrease was observed after 60 min of [3H]-GABA uptake assay at E15, which is accompanied by an increase in [3H]-GABA release. Caffeine increased the protein levels of A1R without altering ADORA1 mRNA and was devoid of effects on A2AR density or ADORA2A mRNA levels. The decrease of GABA uptake promoted by caffeine was reverted by A1R activation with N6-cyclohexyl adenosine (CHA) but not by A2AR activation with CGS 21680. Caffeine exposure increased cAMP levels and GAT-1 protein levels, which was evenly expressed between E11-E15. As expected, we observed an increase of GABA containing amacrine cells and processes in the IPL, also, cAMP pathway blockage by H-89 decreased caffeine mediated [3H]-GABA uptake. Our data support the idea that chronic injection of caffeine alters GABA transport via A1R during retinal development and that the cAMP/PKA pathway plays an important role in the regulation of GAT-1 function.

Caffeine exposure alters adenosine system and neurochemical markers during retinal development.

Evidence points to beneficial properties of caffeine in the adult central nervous system, but teratogenic effects have also been reported. Caffeine exerts most of its effects by antagonizing adenosine receptors, especially A1 and A2A subtypes. In this study, we evaluated the role of caffeine on the expression of components of the adenosinergic system in the developing avian retina and the impact of caffeine exposure upon specific markers for classical neurotransmitter systems. Caffeine exposure (5-30 mg/kg by in ovo injection) to 14-day-old chick embryos increased the expression of A1 receptors and concomitantly decreased A2A adenosine receptors expression after 48 h. Accordingly, caffeine (30 mg/kg) increased [(3) H]-8-cyclopentyl-1,3-dipropylxanthine (A1 antagonist) binding and reduced [(3) H]-ZM241385 (A2A antagonist) binding. The caffeine time-response curve demonstrated a reduction in A1 receptors 6 h after injection, but an increase after 18 and 24 h. In contrast, caffeine exposure increased the expression of A2A receptors from 18 and 24 h. Kinetic assays of [(3) H]-S-(4-nitrobenzyl)-6-thioinosine binding to the equilibrative adenosine transporter ENT1 revealed an increase in Bmax with no changes in Kd , an effect accompanied by an increase in adenosine uptake. Immunohistochemical analysis showed a decrease in retinal content of tyrosine hydroxylase, calbindin and choline acetyltransferase, but not Brn3a, after 48 h of caffeine injection. Furthermore, retinas exposed to caffeine had increased levels of phosphorylated extracellular signal-regulated kinase and cAMP-response element binding protein. Overall, we show an in vivo regulation of the adenosine system, extracellular signal-regulated kinase and cAMP-response element binding protein function and protein expression of specific neurotransmitter systems by caffeine in the developing retina. The beneficial or maleficent effects of caffeine have been demonstrated by the work of different studies. It is known that during animal development, caffeine can exert harmful effects, impairing the correct formation of CNS structures. In this study, we demonstrated cellular and tissue effects of caffeine's administration on developing chick embryo retinas. Those effects include modulation of adenosine receptors (A1 , A2 ) content, increasing in cAMP response element-binding protein (pCREB) and extracellular signal-regulated kinase phosphorylation (pERK), augment of adenosine equilibrative transporter content/activity, and a reduction of some specific cell subpopulations. ENT1, Equilibrative nucleoside transporter 1.