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Diabetic retinopathy is a severe retinal complication that diabetic patients are susceptible to present. Although this disease is currently characterized as a microvascular disease, there is growing evidence that neural changes occur and maybe precede vascular impairments. Using chicken retina, an avascular tissue with no direct contact with blood vessels and neural retina, this study aimed to evaluate the influence of acute exposure to high glucose concentration in the retinal GABAergic system, and the role of nitric oxide (NO) in this modulation. Therefore, in ex vivo experiments, retinas were incubated in control (10 mM glucose) or high glucose condition (35 mM) for 30 min. By using DAF-FM to evaluate NO production, it was possible to show that high glucose (HG) significantly increased NO levels in the outer nuclear layer, inner nuclear layer (outer and inner portion), and inner plexiform layer. It was also observed that HG increased GABA immunoreactivity (IR) in amacrine and horizontal cells. HG did not change glutamic acid decarboxylase-IR, whereas it decreased GABA Transporter (GAT) 1-IR and increased GAT-3-IR. The co-treatment with 7-NI, an inhibitor of neuronal nitric oxide synthase (nNOS), blocked all changes stimulated by HG exposure. The concomitant exposure with SNAP-5114, a GAT-2/3 inhibitor, blocked the increase in GABA-IR caused by HG incubation. Therefore, our data suggest that hyperglycemia induces GABA accumulation in the cytosol by modulating GABA transporters. This response is dependent on NO production and signaling., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Retinal ischemia is a pathological event present in several retinopathies such as diabetic retinopathy and glaucoma, leading to partial or full blindness with no effective treatment available. Since synthetic and endogenous cannabinoids have been studied as modulators of ischemic events in the central nervous system (CNS), the present study aimed to investigate the involvement of cannabinoid system in the cell death induced by ischemia in an avascular (chick) retina. We observed that chick retinal treatment with a combination of WIN 55212-2 and cannabinoid receptor antagonists (either AM251/O-2050 or AM630) decreased the release of lactate dehydrogenase (LDH) induced by retinal ischemia in an oxygen and glucose deprivation (OGD) model. Further, the increased availability of endocannabinoids together with cannabinoid receptor antagonists also had a neuroprotective effect. Surprisingly, retinal exposure to any of these drugs alone did not prevent the release of LDH stimulated by OGD. Since cannabinoids may also activate transient receptor potential (TRP) channels, we investigated the involvement of TRPA1 receptors (TRPA1) in retinal cell death induced by ischemic events. We demonstrated the presence of TRPA1 in the chick retina, and observed an increase in TRPA1 content after OGD, both by western blot and immunohistochemistry. In addition, the selective activation of TRPA1 by mustard oil (MO) did not worsen retinal LDH release induced by OGD, whereas the blockage of TRPA1 completely prevented the extravasation of cellular LDH in ischemic condition. Hence, these results show that during the ischemic event there is an augment of TRPA1, and activation of this receptor is important in cell death induction. The data also indicate that metabotropic cannabinoid receptors, both type 1 and 2, are not involved with the cell death found in the early stages of ischemia. Therefore, the study points to a potential role of TRPA1 as a target for neuroprotective approaches in retinal ischemia., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Fragile X Mental Retardation Protein (FMRP) is a RNA-binding protein that modulates protein synthesis at the synapse and its function is regulated by glutamate. The retina is the first structure that participates in vision, and uses glutamate to transduce electromagnetic signals from light to electrochemical signals to neurons. FMRP has been previously detected in the retina, but its localization has not been studied yet. In this work, our objectives were to describe the localization of FMRP in the retina, to determine whether different exposure to dark or light stimulus alters FMRP expression in the retina, and to compare the pattern in two different species, the mouse and chick. We found that both FMRP mRNA and protein are expressed in the retina. By immunohistochemistry analysis we found that both mouse and chick present similar FMRP expression localized mainly in both plexiform layers and the inner retina. It was also observed that FMRP is down-regulated by 24 h dark adaptation compared to its expression in the retina of animals that were exposed to light for 1 h after 24 h in the dark. We conclude that FMRP is likely to participate in retinal physiology, since its expression changes with light exposure. In addition, the expression pattern and regulation by light of FMRP seems well conserved since it was similar in both mouse and chick., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Diabetic retinopathy (DR), the main cause of blindness among diabetic patients, affects both neuronal and vascular cells of the retina. Studies show that neuronal cell death begins after 4 weeks of diabetes and could be related with an increase in oxidative stress. System [Formula: see text] is a glutamate/cystine exchanger, formed by a catalytic subunit called xCT and a regulatory subunit 4F2hc, whose activity is crucial to the synthesis of glutathione, which is a key antioxidant molecule for cells. Although some studies have shown that glutamate transport mediated by excitatory amino acid transporters (EAATs) in diabetic rats is downregulated, there are no studies investigating system [Formula: see text] in this context. To evaluate whether system [Formula: see text] is modified by early onset of diabetes, primary retinal cell culture exposed to high glucose and retinas of rats 3 weeks after streptozotocin injection were used. We observed that xCT subunit protein expression both in cultures and in vivo were diminished. Furthermore, system [Formula: see text] activity and GSH levels were also decreased whereas oxidative stress was increased in retinas of diabetic animals. Therefore, this study raises the possibility that alterations in system [Formula: see text] expression and activity could occur during early onset of diabetes. In that way, system [Formula: see text] modifications could be related to increased ROS in diabetic retinopathy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)