Role of monocarboxylate transporters in AMPK-mediated protection against excitotoxic injury in the rat retina.

Activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway protects against N-methyl-D-aspartic acid (NMDA)-induced excitotoxic retinal injury. AMPK activation enhances fatty acid metabolism and ketone body synthesis. Ketone bodies are transported into neurons by monocarboxylate transporters (MCTs) and exert neuroprotective effects. In this study, we examined the distribution and expression levels of MCT1 and MCT2 in the retina and analyzed the effects of pharmacological inhibition of MCTs on the protective effects of metformin and 5-aminoimidazole-4-carboxamide (AICAR), activators of AMPK, against NMDA-induced retinal injury in rats. MCT1 was expressed in the blood vessels, processes of astrocytes and Müller cells, and inner segments of photoreceptors in the rat retina, whereas MCT2 was expressed in neuronal cells in the ganglion cell layer (GCL) and in astrocyte processes. The expression levels of MCT2, but not MCT1, decreased one day after intravitreal injection of NMDA (200 nmol). Intravitreal injection of NMDA decreased the number of cells in the GCL compared to the vehicle seven days after injection. Simultaneous injection of metformin (20 nmol) or AICAR (50 nmol) with NMDA attenuated NMDA-induced cell loss in the GCL, and these protective effects were attenuated by AR-C155858 (1 pmol), an inhibitor of MCTs. AR-C155858 alone had no significant effect on the retinal structure. These results suggest that AMPK-activating compounds protect against NMDA-induced excitotoxic retinal injury via mechanisms involving MCTs in rats. NMDA-induced neurotoxicity may be associated with retinal neurodegenerative changes in glaucoma and diabetic retinopathy. Therefore, AMPK-activating compounds may be effective in managing these retinal diseases.

Systemic medications for sickle cell disease and potential applications for sickle cell retinopathy.

PURPOSE OF REVIEW: To review the literature evaluating systemic medications for treatment of sickle cell disease (SCD) and their applications for sickle cell retinopathy. RECENT FINDINGS: Prior studies have demonstrated the efficacy of traditional systemic therapies in reducing the risk of development of sickle cell retinopathy. Since 2017, several new and promising disease-modifying therapies for sickle cell disease have been approved for clinical use, including the first genetic therapies such as exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel). These treatments have shown promising results for systemic management but are not widely utilized due to limited access and high cost. The efficacy of these therapies for the prevention of sickle cell retinopathy remains unknown and opens the door to new avenues for research. Furthermore, the role of systemic therapy for the management of hemoglobin SC (HbSC) disease, which has milder systemic effects but higher likelihood of causing retinopathy, remains poorly understood. SUMMARY: Hydroxyurea has been a mainstay of systemic management of SCD with prior work suggesting its ability to reduce the likelihood of developing retinopathy. There are several new and potentially curative systemic therapies for SCD, though their role in retinopathy prevention and management has not been studied extensively. Future studies are necessary to understand the implications of these emerging therapies for sickle cell retinopathy.

Stem cell factor protects against chronic ischemic retinal injury by modulating on neurovascular unit.

Retinal ischemia is a significant factor in various vision-threatening diseases, but effective treatments are currently lacking. This study explores the potential of stem cell factor (SCF) in regulating the neurovascular unit as a therapeutic intervention for retinal ischemic diseases. A chronic retinal ischemia model was established in Brown Norway rats using bilateral common carotid artery occlusion (BCCAO). Subsequent SCF treatment resulted in a remarkable recovery of retinal function, as indicated by electroretinogram, light/dark transition test, and optokinetic head tracking test results. Histological examination demonstrated a significant increase in the number of retinal neurons and an overall thickening of the retina. Immunofluorescence confirmed these findings and further demonstrated that SCF treatment regulated retinal remodeling. Notably, SCF treatment ameliorated the disrupted expression of synaptic markers in the control group's BCCAO rats and suppressed the activation of Müller cells and microglia. Retinal whole-mount analysis revealed a significant improvement in the abnormalities in retinal vasculature following SCF treatment. Transcriptome sequencing analysis revealed that SCF-induced transcriptome changes were closely linked to the Wnt7 pathway. Key members of the Wnt7 pathway, exhibited significant upregulation following SCF treatment. These results underscore the protective role of SCF in the neurovascular unit of retinal ischemia rats by modulating the Wnt7 pathway. SCF administration emerges as a promising therapeutic strategy for retinal ischemia-related diseases, offering potential avenues for future clinical interventions.

N-Acetylserotonin Alleviates Retinal Autophagy via TrkB/AKT/Nrf2 Signaling Pathway in Retinal Ischemia-Reperfusion Injury Rats.

INTRODUCTION: The objective of this study was to investigate the impact of N-acetylserotonin (NAS) on the autophagy of retinal cells in rats with retinal ischemia-reperfusion injury (RIRI) and to explore the mechanisms by which NAS administration can alleviate RIRI through the tropomyosin-related kinase receptor B (TrkB)/protein kinase B (Akt)/nuclear factor erythroid-derived factor 2-related factor (Nrf2) signaling pathway. METHODS: Healthy adult male rats were randomly assigned to four groups: sham, RIRI, RIRI+NAS, and RIRI+NAS+ANA-12. The RIRI group was induced by elevating intraocular pressure, and changes in retinal structure and edema were assessed using H&E staining. The RIRI+NAS and RIRI+NAS+ANA-12 groups received intraperitoneal injections of NAS before and after modeling. The RIRI+NAS+ANA-12 group was also administered ANA-12, a TrkB antagonist. Immunohistochemical staining and Western blot analysis were used to evaluate phosphorylated TrkB (p-TrkB), phosphorylated Akt (p-Akt), Nrf2, sequestosome 1 (P62), and microtubule-associated protein 1 light chain 3 (LC3-II) levels in the retinas of each group. Electroretinogram was recorded to detect retinal function in each group of rats 24 h after modeling. RESULTS: The RIRI+NAS group had a thinner retina and more retinal ganglion cells (RGCs) than RIRI and RIRI+NAS+ANA-12 groups (p < 0.05). Immunohistochemical staining and Western blot results showed that p-TrkB, p-Akt, n-Nrf2, and P62 levels in the RIRI+NAS group were higher compared with those in RIRI and RIRI+NAS+ANA-12 groups (p < 0.05). Also, lower LC3-II levels were observed in the RIRI+NAS group compared with that in RIRI and RIRI+NAS+ANA-12 groups (p < 0.05). Electroretinogram recording results showed that 24 h after retinal ischemia-reperfusion, the magnitude of b-wave changes was attenuated in the RIRI+NAS group compared with the RIRI group (p < 0.05). CONCLUSION: The administration of NAS activates the TrkB/Akt/Nrf2 signaling pathway, reduces autophagy, alleviates retinal edema, promotes the survival of retinal ganglion cells (RGCs), and provides neuroprotection against retinal injury.

GSK840 Alleviates Retinal Neuronal Injury by Inhibiting RIPK3/MLKL-Mediated RGC Necroptosis After Ischemia/Reperfusion.

Purpose: This study aimed to explore the impact of GSK840 on retinal neuronal injury after retinal ischemia/reperfusion (IR) and its associated mechanism. Methods: We established an in vivo mouse model of IR and an in vitro model of oxygen and glucose deprivation/reoxygenation (OGDR) in primary mouse retinal ganglion cells (RGCs). GSK840, a small-molecule compound, was used to specifically inhibit RIPK3/MLKL-dependent necroptosis. Retinal structure and function evaluation was performed by using hematoxylin and eosin staining, optical coherence tomography, and electroretinography. Propidium Iodide (PI) staining was used for detection of necroptotic cell death, whereas Western blot analysis and immunofluorescence were used to assess necroptosis-related proteins and inner retinal neurons. Results: RIPK3/MLKL-dependent necroptosis was rapidly activated in RGCs following retinal IR or OGDR. GSK840 helped maintain relatively normal inner retinal structure and thickness by preserving inner retinal neurons, particularly RGCs. Meanwhile, GSK840 ameliorated IR-induced visual dysfunction, as evidenced by the improved amplitudes of photopic negative response, a-wave, b-wave, and oscillatory potentials. And GSK840 treatment significantly reduced the population of PI+ RGCs after injury. Mechanistically, GSK840 ameliorated RGC necroptosis by inhibiting the RIPK3/MLKL pathway. Conclusions: GSK840 exerts protective effects against retinal neuronal injury after IR by inhibiting RIPK3/MLKL-mediated RGC necroptosis. GSK840 may represent a protective strategy for RGC degeneration in ischemic retinopathy.

PERK Inhibition Suppresses Neovascularization and Protects Neurons During Ischemia-Induced Retinopathy.

Purpose: Retinal ischemia is a common cause of a variety of eye diseases, such as retinopathy of prematurity, diabetic retinopathy, and vein occlusion. Protein kinase RNA-activated-like endoplasmic reticulum (ER) kinase (PERK), one of the main ER stress sensor proteins, has been involved in many diseases. In this study, we investigated the role of PERK in ischemia-induced retinopathy using a mouse model of oxygen-induced retinopathy (OIR). Methods: OIR was induced by subjecting neonatal pups to 70% oxygen at postnatal day 7 (P7) followed by returning to room air at P12. GSK2606414, a selective PERK inhibitor, was orally administrated to pups right after they were returned to room air once daily until 1 day before sample collection. Western blot, immunostaining, and quantitative PCR were used to assess PERK phosphorylation, retinal changes, and signaling pathways in relation to PERK inhibition. Results: PERK phosphorylation was prominently increased in OIR retinas, which was inhibited by GSK2606414. Concomitantly, PERK inhibition significantly reduced retinal neovascularization (NV) and retinal ganglion cell (RGC) loss, restored astrocyte network, and promoted revascularization. Furthermore, PERK inhibition downregulated the recruitment/proliferation of mononuclear phagocytes but did not affect OIR-upregulated canonical angiogenic pathways. Conclusions: Our results demonstrate that PERK is involved in ischemia-induced retinopathy and its inhibition using GSK2606414 could offer an effective therapeutic intervention aimed at alleviating retinal NV while preventing neuron loss during retinal ischemia.

AMP kinase activation by Omega-3 polyunsaturated fatty acid protects the retina against ischemic insult: An in vitro and in vivo study.

PURPOSE: To investigate the possible beneficial effects of omega-3 polyunsaturated fatty acids (ω3-PUFAs) in ischemic retinal angiogenesis and whether AMP-activated protein kinase (AMPK) is involved. METHODS: Human retinal microvascular endothelial cells (hRMECs) were exposed to dimethyloxalylglycine (DMOG), a hypoxia-inducible factor hydroxylase inhibitor, in the presence or absence of docosahexaenoic acid (DHA) and small interfering RNA (siRNA) for AMPKα for 24 h. Ischemic factors, endothelial mesenchymal transition marker, endothelial barrier integrity, cell migration, and tube formation were evaluated. Neonatal AMPKα2-/- and control wild-type (WT) mice were submitted to an oxygen-induced retinopathy (OIR) protocol; their nursing mother mice were either fed ω3-PUFAs or not. In the end, ischemic markers and endothelial cell proliferation were evaluated in neonatal mouse retinal tissue through immunohistochemical or immunofluorescent assays among all studied groups. RESULTS: Cells exposed to DMOG displayed increased expressions of hypoxic and endothelial mesenchymal transition (vimentin) markers and barrier disarrangement of Zonula Occludens-1 compared to the control, accompanied by increased cellular migration and tube formation (p < 0.05). AMPK activity was significantly decreased. Supplementation with DHA restored the mentioned alterations compared to DMOG (p<0.05). In siRNAAMPKα-treated cells, the beneficial effects observed with DHA were abolished. DHA upregulated G-protein receptor-120 (GPR120), which promptly increased intracellular levels of calcium (p ≤ 0.001), which consequently increased Calcium/calmodulin-dependent protein kinase kinase ß expression (CaMKKß) thus phosphorylating AMPKThr172. AMPKα2-/- and wild-type (WT) OIR mice exhibited similar retinal ischemic changes, and the oral supplementation with ω3-PUFA efficiently prevented the noticed ischemic alterations only in WT mice, suggesting that AMPKα2 is pivotal in the protective effects of ω3-PUFA. CONCLUSIONS: ω3-PUFAs protect the retina from the effects of ischemic conditions, and this effect occurs via the GPR120-CaMKKß-AMPK axis. A better understanding of this mechanism might improve the control of pathological angiogenesis in retinal ischemic diseases.

[Radiation-induced retinopathy: actual knowledge and new concepts]. / La rétinopathie radique : données actuelles et perspectives.

Radiation retinopathy is an occlusive vascular pathology following radiotherapy, generally targeted on the eye or peri-ocular structures. Despite increasingly precise techniques (stereotactic radiosurgery, proton therapy, etc.), the inclusion of the retina in the radiation field is sometimes unavoidable. This can lead to a severe pathology, which can ultimately cause blindness or even the anatomical loss of the eye when neovascular glaucoma occurs, due to the abnormal proliferation of neovessels. Radiation retinopathy have been described for more than a century, but it has recently seen great advances in both diagnosis and treatment. The advances of efficient and less invasive examinations in our clinical practice, such as OCT-angiography, allows for easier screening and diagnosis at earlier stages. Thus a new approach to the pathology is necessary, first of all through new definitions and classifications including previously undetected minimal forms. Furthermore, the recent appearance of intravitreal therapies by injection of anti-VEGF or dexamethasone implants has drastically changed the visual prognosis of these patients, who were previously treated only by retinal photocoagulation of the ischaemic areas. Recent studies have even shown the effectiveness of these new molecules in preventing the development of radiation retinopathy. This review of the literature provides an update on this disease and details how these recent diagnostic and therapeutic developments may play a role in the management of this complication.

Intravitreal Injection of PACAP Attenuates Acute Ocular Hypertension-Induced Retinal Injury Via Anti-Apoptosis and Anti-Inflammation in Mice.

Purpose: Pituitary adenylate cyclase-activating polypeptide (PACAP) has shown potent neuroprotective effects in central nervous system and retina disorders. However, whether PACAP can attenuate retinal neurodegeneration induced by acute ocular hypertension (AOH) and the underlying mechanisms remain unknown. In this study, we aimed to investigate the effects of PACAP on the survival and function of retinal ganglion cells (RGCs), apoptosis, and inflammation in a mouse model of AOH injury. Methods: PACAP was injected into the vitreous body immediately after inducing AOH injury. Hematoxylin and eosin staining and optical coherence tomography were used to evaluate the loss of retina tissue. Pattern electroretinogram was used to evaluate the function of RGCs. TUNEL assay was used to detect apoptosis. Immunofluorescence and western blot were employed to evaluate protein expression levels. Results: PACAP treatment significantly reduced the losses of whole retina and inner retina thicknesses, Tuj1-positive RGCs, and the amplitudes of pattern electroretinograms induced by AOH injury. Additionally, PACAP treatment remarkably reduced the number of TUNEL-positive cells and inhibited the upregulation of Bim, Bax, and cleaved caspase-3 and downregulation of Bcl-xL after AOH injury. Moreover, PACAP markedly inhibited retinal reactive gliosis and vascular inflammation, as demonstrated by the downregulation of GFAP, Iba1, CD68, and CD45 in PACAP-treated mice. Furthermore, upregulated expression of NF-κB and phosphorylated NF-κB induced by AOH injury was attenuated by PACAP treatment. Conclusions: PACAP could prevent the loss of retinal tissue and improve the survival and function of RGCs. The neuroprotective effect of PACAP is probably associated with its potent anti-apoptotic and anti-inflammatory effects.

Intravitreal Trans-Resveratrol Ameliorates NMDA-Induced Optic Nerve and Retinal Injury.

PURPOSE: Retinal and optic nerve damage in glaucoma involves excitotoxicity via N-methyl-D-aspartate (NMDA) receptors. Since, trans-resveratrol (TR) is known to provide neuroprotection, we investigated its protective effects against NMDA-induced retinal and optic nerve injury. METHODS: Sprague Dawley rats were divided into four groups which received vehicle (PBS), NMDA, and TR 0.4 or TR 4 nmol 24 h prior to NMDA, unilaterally and intravitreally. Seven days post-injection, rats were euthanized; eyeballs were enucleated and subjected to hematoxylin and eosin and terminal transferase dUTP nick end labeling staining while optic nerves were isolated for toluidine blue staining. RESULTS: Retinal morphometry showed that ganglion cell layer (GCL) layer thickness within inner retina (IR), retinal cell count (RCC) per 100-µm length of GCL, RCC per 100-µm2 area of GCL, and RCC per 100 µm2 of IR were significantly higher in both TR-treated groups compared to the NMDA group. No differences were observed between the two dose groups. Optic nerve morphology was in accordance with the retinal morphology whereby TR-treated groups showed significantly lesser degenerative changes compared to NMDA-treated group. CONCLUSIONS: TR protects against NMDA-induced changes in retinal and optic nerve morphology by preventing retinal cell apoptosis.

The potential of marine resources for retinal diseases: a systematic review of the molecular mechanisms.

We rely on vision more than on any other sense to obtain information about our environment. Hence, the loss or even impairment of vision profoundly affects our quality of life. Diet or food components have already demonstrated beneficial effects on the development of retinal diseases. Recently, there has been a growing interest in resources from marine animals and plants for the prevention of retinal diseases through nutrition. Especially fish intake and omega-3 fatty acids have already led to promising results, including associations with a reduced incidence of retinal diseases. However, the underlying molecular mechanisms are insufficiently explained. The aim of this review was to summarize the known mechanistic effects of marine resources on the pathophysiological processes in retinal diseases. We performed a systematic literature review following the PRISMA guidelines and identified 107 studies investigating marine resources in the context of retinal diseases. Of these, 46 studies described the underlying mechanisms including anti-inflammatory, antioxidant, antiangiogenic/vasoprotective, cytoprotective, metabolic, and retinal function effects, which we critically summarize. We further discuss perspectives on the use of marine resources for human nutrition to prevent retinal diseases with a particular focus on regulatory aspects, health claims, safety, and bioavailability.

Pinosylvin Extract Retinari™ Sustains Electrophysiological Function, Prevents Thinning of Retina, and Enhances Cellular Response to Oxidative Stress in NFE2L2 Knockout Mice.

Chronic oxidative stress eventually leads to protein aggregation in combination with impaired autophagy, which has been observed in age-related macular degeneration. We have previously shown an effective age-related macular degeneration disease model in mice with nuclear factor-erythroid 2-related factor-2 (NFE2L2) knockout. We have also shown pinosylvin, a polyphenol abundant in bark waste, to increase human retinal pigment epithelium cell viability in vitro. In this work, the effects of commercial natural pinosylvin extract, Retinari™, were studied on the electroretinogram, optical coherence tomogram, autophagic activity, antioxidant capacity, and inflammation markers. Wild-type and NFE2L2 knockout mice were raised until the age of 14.8 ± 3.8 months. They were fed with either regular or Retinari™ chow (141 ± 17.0 mg/kg/day of pinosylvin) for 10 weeks before the assays. Retinari™ treatment preserved significant retinal function with significantly preserved a- and b-wave amplitudes in the electroretinogram responses. Additionally, the treatment prevented thinning of the retina in the NFE2L2 knockout mice. The NFE2L2 knockout mice showed reduced ubiquitin-tagged protein accumulation in addition to local upregulation of complement factor H and antioxidant enzymes superoxide dismutase 1 and catalase. Therefore, the treatment in the NFE2L2 KO disease model led to reduced chronic oxidative stress and sustained retinal function and morphology. Our results demonstrate that pinosylvin supplementation could potentially lower the risk of age-related macular degeneration onset and slow down its progression.

COVID-19 and the Eye: Ocular Manifestations, Treatment and Protection Measures.

The novel pandemic coronavirus disease 2019 (COVID-19) leading to health and economic problems worldwide is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although COVID-19 mainly occurs as a lower respiratory tract infection, there is multiorgan involvement in infected patients. The disease is transmitted from person to person through air droplets or contact with contaminated surfaces. SARS-CoV-2 leads to this systemic involvement by attaching to angiotensin-converting enzyme 2 (ACE2) receptors located on several human cells. Since SARS-CoV-2 RNA has been found in tears of infected patients, ocular surface may allow the virus to transmit to nasopharynx via the nasolacrimal duct. This narrative review aims to sum up all segmental ocular complications, ocular adverse effects of COVID-19 treatment, and preventive measures suggested to minimize the SARS-CoV-2 transmission between patients and ophthalmologists by reviewing currently available literature.

Pemafibrate Prevents Retinal Dysfunction in a Mouse Model of Unilateral Common Carotid Artery Occlusion.

Cardiovascular diseases lead to retinal ischemia, one of the leading causes of blindness. Retinal ischemia triggers pathological retinal glial responses and functional deficits. Therefore, maintaining retinal neuronal activities and modulating pathological gliosis may prevent loss of vision. Previously, pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, was nominated as a promising drug in retinal ischemia. However, a protective role of pemafibrate remains untouched in cardiovascular diseases-mediated retinal ischemia. Therefore, we aimed to unravel systemic and retinal alterations by treating pemafibrate in a new murine model of retinal ischemia caused by cardiovascular diseases. Adult C57BL/6 mice were orally administered pemafibrate (0.5 mg/kg) for 4 days, followed by unilateral common carotid artery occlusion (UCCAO). After UCCAO, pemafibrate was continuously supplied to mice until the end of experiments. Retinal function (a-and b-waves and the oscillatory potentials) was measured using electroretinography on day 5 and 12 after UCCAO. Moreover, the retina, liver, and serum were subjected to qPCR, immunohistochemistry, or ELISA analysis. We found that pemafibrate enhanced liver function, elevated serum levels of fibroblast growth factor 21 (FGF21), one of the neuroprotective molecules in the eye, and protected against UCCAO-induced retinal dysfunction, observed with modulation of retinal gliosis and preservation of oscillatory potentials. Our current data suggest a promising pemafibrate therapy for the suppression of retinal dysfunction in cardiovascular diseases.

Salidroside Prevents Hypoxia-Induced Human Retinal Microvascular Endothelial Cell Damage Via miR-138/ROBO4 Axis.

Purpose: Retinopathies are associated with the injury of retinal microvascular endothelial cells. Salidroside (SAL) is a medicinal supplement that has antioxidative and cytoprotective properties. We hypothesized that SAL might have a protective function in retinopathies. This research aims to explore the function and mechanism of SAL in hypoxia-induced retinal microvascular endothelial cell injury. Methods: Human retinal microvascular endothelial cells (HRMECs) injury was induced by culturing under hypoxic condition. The function of SAL on HRMECs injury was investigated using cell counting kit-8, 5-ethynyl-2'-deoxyuridine (EdU) staining, flow cytometry, Western blotting, and enzyme linked immunosorbent assay. MicroRNA (miR)-138, roundabout 4 (ROBO4), and proteins in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways were examined using quantitative reverse transcription polymerase chain reaction or Western blotting. The target correlation was determined by dual-luciferase reporter analysis and RNA immunoprecipitation. Results: Hypoxia resulted in proliferation inhibition, cycle arrest, apoptosis, inflammatory reaction, and oxidative stress in HRMECs. SAL attenuated hypoxia-induced HRMECs injury via increasing cell proliferation, and mitigating cycle arrest, apoptosis, inflammatory reaction, and oxidative stress. MiR-138 expression was enhanced by hypoxia, and decreased via SAL stimulation. MiR-138 upregulation reversed the influence of SAL on hypoxia-induced HRMECs injury. ROBO4 was targeted via miR-138. ROBO4 overexpression weakened the role of miR-138 in HRMECs injury. The PI3K/AKT/mTOR pathway was inactivated under hypoxic condition, and SAL increased the activation of PI3K/AKT/mTOR pathways by decreasing miR-138. Conclusions: SAL protected against hypoxia-induced HRMECs injury through regulating miR-138/ROBO4 axis, indicating the protective potential of SAL in retinopathies.

NK-lysin peptides ameliorate viral encephalopathy and retinopathy disease signs and provide partial protection against nodavirus infection in European sea bass.

Antimicrobial peptides (AMP) comprise a wide range of small molecules with direct antibacterial activity and immunostimulatory role and are proposed as promising substitutes of the antibiotics. Additionally, they also exert a role against other pathogens such as viruses and fungi less evaluated. NK-lysin, a human granulysin orthologue, possess a double function, taking part in the innate immunity as AMP and also as direct effector in the cell-mediated cytotoxic (CMC) response. This molecule is suggested as a pivotal molecule involved in the defence upon nervous necrosis virus (NNV), an epizootic virus provoking serious problems in welfare and health status in Asian and Mediterranean fish destined to human consumption. Having proved that NK-lysin derived peptides (NKLPs) have a direct antiviral activity against NNV in vitro, we aimed to evaluate their potential use as a prophylactic treatment for European sea bass (Dicentrarchus labrax), one of the most susceptible cultured-fish species. Thus, intramuscular injection of synthetic NKLPs resulted in a very low transcriptional response of some innate and adaptive immune markers. However, the injection of NKLPs ameliorated disease signs and increased fish survival upon challenge with pathogenic NNV. Although NKLPs showed promising results in treatments against NNV, more efforts are needed to understand their mechanisms of action and their applicability to the aquaculture industry.

RETINAL MICROVASCULAR CHANGES IN UVEAL MELANOMA FOLLOWING CONBERCEPT INJECTION AFTER PLAQUE RADIOTHERAPY AS DETECTED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To investigate macular microvascular characteristics imaged by optical coherence tomography angiography in patients with uveal melanoma following conbercept injections after plaque radiotherapy. METHODS: Prospective comparative analysis comprising 15 patients with uveal melanoma with conbercept injections and 30 patients without conbercept injections after plaque radiotherapy by optical coherence tomography angiography. The conbercept group received intravitreal conbercept injections at the time of plaque removal, 1 month, 3 months, 6 months , 9 months and 12 months after plaque removal (total, 6 injections). The control group had no intravitreal conbercept injection. RESULTS: After initiation of conbercept injections, superficial retinal vascular density in the whole image and parafoveal region were significantly higher at 6 months, whereas there was no significant difference at 9 months and 12 months. In analysis of variance analysis, superficial retinal vascular density in the whole image remained stable after conbercept injections (P = 0.069), whereas the superficial retinal vascular density decreased significantly after plaque radiotherapy in the control group (P = 0.011). In multivariable linear regression, a higher superficial retinal vascular density in the whole image region at 6 months was significantly associated with intravitreal conbercept injection (P = 0.018), wider tumor base (P = 0.026), and thinner tumor thickness (P = 0.04). CONCLUSION: Optical coherence tomography angiography can provide a quantitative evaluation of early retinal microvascular changes after radiotherapy. Intravitreal conbercept treatment could partly relieve the retinal vascular damage in response to radiation therapy at early stage in patients with uveal melanoma; however, it may not be able to provide long-term positive functional outcomes.

Metformin Protects against NMDA-Induced Retinal Injury through the MEK/ERK Signaling Pathway in Rats.

Metformin, an anti-hyperglycemic drug of the biguanide class, exerts positive effects in several non-diabetes-related diseases. In this study, we aimed to examine the protective effects of metformin against N-methyl-D-aspartic acid (NMDA)-induced excitotoxic retinal damage in rats and determine the mechanisms of its protective effects. Male Sprague-Dawley rats (7 to 9 weeks old) were used in this study. Following intravitreal injection of NMDA (200 nmol/eye), the number of neuronal cells in the ganglion cell layer and parvalbumin-positive amacrine cells decreased, whereas the number of CD45-positive leukocytes and Iba1-positive microglia increased. Metformin attenuated these NMDA-induced responses. The neuroprotective effect of metformin was abolished by compound C, an inhibitor of AMP-activated protein kinase (AMPK). The AMPK activator, AICAR, exerted a neuroprotective effect in NMDA-induced retinal injury. The MEK1/2 inhibitor, U0126, reduced the neuroprotective effect of metformin. These results suggest that metformin protects against NMDA-induced retinal neurotoxicity through activation of the AMPK and MEK/extracellular signal-regulated kinase (ERK) signaling pathways. This neuroprotective effect could be partially attributable to the inhibitory effects on inflammatory responses.