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OBJECTIVE: In monogenic diabetes due to KCNJ11 and ABCC8 mutations that impair KATP- channel function, sulfonylureas improve long-term glycemic control. Although KATP channels are extensively expressed in the brain, the effect of sulfonylureas on neurological function has varied widely. We evaluated published evidence about potential effects of sulfonylureas on neurological features, especially epilepsy, cognition, motor function and muscular tone, visuo-motor integration, and attention deficits in children and adults with KCNJ11 and ABCC8-related neonatal-onset diabetes mellitus. RESEARCH DESIGN AND METHODS: We conducted a systematic review and meta-analyses of the literature (PROSPERO, CRD42021254782), including individual-patient data, according to PRISMA, using RevMan software. We also graded the level of evidence. RESULTS: We selected 34 of 776 publications. The evaluation of global neurological function before and after sulfonylurea (glibenclamide) treatment in 114 patients yielded a risk difference (RD) of 58% (95%CI, 43%-74%; I2 = 54%) overall and 73% (95%CI, 32%-113%; I2 = 0%) in the subgroup younger than 4 years; the level of evidence was moderate and high, respectively. EEG studies of epilepsy showed a RD of 56% (95%CI, 23%-89%; I2 = 34%) in patients with KCNJ11 mutations, with a high quality of evidence. For hypotonia and motor function, the RDs were 90% (95%CI, 69%-111%; I2 = 0%) and 73% (95%CI, 35%-111%; I2 = 0%), respectively, with a high level of evidence. CONCLUSIONS: Glibenclamide significantly improved neurological abnormalities in patients with neonatal-onset diabetes due to KCNJ11 or ABCC8 mutations. Hypotonia was the symptom that responded best. Earlier treatment initiation was associated with greater benefits.
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Diabetes Mellitus , Epilepsia , Enfermedades del Recién Nacido , Canales de Potasio de Rectificación Interna , Adulto , Niño , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/genética , Epilepsia/genética , Gliburida , Humanos , Recién Nacido , Enfermedades del Recién Nacido/tratamiento farmacológico , Enfermedades del Recién Nacido/genética , Canales KATP/genética , Hipotonía Muscular , Mutación , Canales de Potasio de Rectificación Interna/genética , Compuestos de Sulfonilurea/uso terapéutico , Receptores de Sulfonilureas/genéticaRESUMEN
BACKGROUND: Results of genetic have led to off-label glibenclamide treatment in patients with neonatal diabetes (NDM) because of potassium channel mutations. No pediatric form of glibenclamide was available. Glibenclamide was designated an orphan drug designation for NDM and a suspension was developed. As a part of the pediatric plan investigation, we assessed its acceptability, efficiency, and safety. METHODS: In this Phase II, prospective, non-randomized, single-center study, patient received glibenclamide tablets for 1 month then the suspension for 3 months. We assessed acceptability using hedonic scales and patient questionnaires, effectiveness using glycated hemoglobin (HbA1C) assays and safety based on hypo and hyperglycemia, and other adverse events. RESULTS: We included 10 patients (0.1-16.2 years, 6 < 5 years) were included. Younger patients preferred the suspension and older the tablets. All parents were satisfied with the ease of suspension administration. The parents of 5 of 6 younger children preferred the suspension over the tablets and kept it. Switching from tablets to suspension did not affect the excellent metabolic control (median HbA1c change, -0.40%, [-1.3% to 0.5%] P = 0.08). Median frequencies of hypoglycemia and hyperglycemia were less than 5% of routine blood glucose assays and were similar with both dosage forms. Two patients each experienced one episode of hypoglycemia below 35 mg/dL highlighting the need for dosage titration when switching from tablets to suspension. Transient and non-severe abdominal pain or diarrhea occurred in three patients. None of the patients discontinued the treatment. CONCLUSION: The glibenclamide oral suspension Amglidia, the first anti-diabetic drug specifically developed for pediatric patients, is acceptable, effective, and safe in patients with NDM (NCT02375828). CLINICAL TRIAL REGISTRATION: Glibentek in Patients with Neonatal Diabetes Secondary to Mutations in K + -ATP Channels, clinicaltrials.gov, NCT02375828, https://clinicaltrials.gov/ct2/show/NCT02375828.
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Diabetes Mellitus/congénito , Diabetes Mellitus/tratamiento farmacológico , Gliburida/administración & dosificación , Hipoglucemiantes/administración & dosificación , Enfermedades del Recién Nacido/tratamiento farmacológico , Administración Oral , Adolescente , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Niño , Preescolar , Femenino , Gliburida/efectos adversos , Humanos , Hipoglucemiantes/efectos adversos , Lactante , Recién Nacido , Masculino , Aceptación de la Atención de Salud , Suspensiones , Comprimidos , Resultado del TratamientoRESUMEN
We have identified and characterized a spontaneous Brown Norway from Janvier rat strain (BN-J) presenting a progressive retinal degeneration associated with early retinal telangiectasia, neuronal alterations, and loss of retinal Müller glial cells resembling human macular telangiectasia type 2 (MacTel 2), which is a retinal disease of unknown cause. Genetic analyses showed that the BN-J phenotype results from an autosomal recessive indel novel mutation in the Crb1 gene, causing dislocalization of the protein from the retinal Müller glia (RMG)/photoreceptor cell junction. The transcriptomic analyses of primary RMG cultures allowed identification of the dysregulated pathways in BN-J rats compared with wild-type BN rats. Among those pathways, TGF-ß and Kit Receptor Signaling, MAPK Cascade, Growth Factors and Inflammatory Pathways, G-Protein Signaling Pathways, Regulation of Actin Cytoskeleton, and Cardiovascular Signaling were found. Potential molecular targets linking RMG/photoreceptor interaction with the development of retinal telangiectasia are identified. This model can help us to better understand the physiopathologic mechanisms of MacTel 2 and other retinal diseases associated with telangiectasia.
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Células Ependimogliales/patología , Proteínas del Ojo/genética , Mutación/genética , Degeneración Retiniana , Telangiectasia/complicaciones , Telangiectasia/genética , Factores de Edad , Animales , Animales Recién Nacidos , Células Cultivadas , Modelos Animales de Enfermedad , Electrorretinografía , Células Ependimogliales/metabolismo , Células Ependimogliales/ultraestructura , Proteínas del Ojo/metabolismo , Angiografía con Fluoresceína , Proteína Ácida Fibrilar de la Glía/metabolismo , Neuronas/patología , Neuronas/ultraestructura , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Ratas , Ratas Mutantes , Degeneración Retiniana/etiología , Degeneración Retiniana/genética , Degeneración Retiniana/patología , Vasos Retinianos/patología , Vasos Retinianos/ultraestructura , Transducción de Señal/fisiología , Vías Visuales/patología , Vías Visuales/ultraestructuraRESUMEN
PURPOSE: Intravitreal recombinant tissue plasminogen activator (rtPA) is used off-label for the surgical management of submacular hemorrhage, a severe complication of neovascular age-related macular degeneration. rtPA is approved for coronary and cerebral thrombolysis. However, in ischemic stroke rtPA is known to increase excitotoxic neural cell death by interacting with the N-methyl-D-aspartate (NMDA) receptor. We therefore investigated the retinal toxicity of rtPA in healthy rats and in a model of NMDA-induced retinal excitotoxicity. METHODS: First, rtPA at three different doses (2.16 µg/5 µl, 0.54 µg/5 µl, and 0.27 µg/5 µl) or vehicle (NaCl 0.9%) was injected intravitreally in healthy rat eyes. Electroretinograms (ERGs) were performed at 24 h or 7 days. Annexin V-fluorescein isothiocyanate (FITC)-labeled apoptotic retinal ganglion cells (RGCs) were counted on flatmounted retinas at 24 h or 7 days. Next, NMDA + vehicle or NMDA + rtPA (0.27 µg/5 µl) was injected intravitreally to generate excitotoxic conditions. Apoptotic annexin V-FITC-labeled RGCs and surviving Brn3a-labeled RGCs were quantified on flatmounted retinas and radial sections, 18 h after treatment. RESULTS: In healthy rat eyes, the number of apoptotic RGCs was statistically significantly increased 24 h after the administration of rtPA at the highest dose (2.16 µg/5 µl; p = 0.0250) but not at the lower doses of 0.54 and 0.27 µg/5 µl (p = 0.36 and p = 0.20), compared to vehicle. At day 7, there was no difference in the apoptotic RGC count between the rtPA- and vehicle-injected eyes (p = 0.70, p = 0.52, p = 0.11). ERG amplitudes and implicit times were not modified at 24 h or 7 days after injection of any tested rtPA doses, compared to the baseline. Intravitreal administration of NMDA induced RGC death, but under these excitotoxic conditions, coadministration of rtPA did not increase the number of dead RGCs (p = 0.70). Similarly, the number of surviving RGCs on the flatmounted retinas and retinal sections did not differ between the eyes injected with NMDA + vehicle and NMDA + rtPA (p = 0.59 and p = 0.67). CONCLUSIONS: At low clinical equivalent doses corresponding to 25 µg/0.1 ml in humans, intravitreal rtPA is not toxic for healthy rat retinas and does not enhance NMDA-induced excitotoxicity. Vitreal equivalent doses ≥200 µg/0.1 ml should be avoided in patients, due to potential RGC toxicity.
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Neurotoxinas/toxicidad , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacología , Activador de Tejido Plasminógeno/efectos adversos , Activador de Tejido Plasminógeno/farmacología , Animales , Apoptosis/efectos de los fármacos , Electrorretinografía , Inyecciones Intravítreas , Masculino , Ratas Long-Evans , Proteínas Recombinantes/administración & dosificación , Retina , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismo , Activador de Tejido Plasminógeno/administración & dosificaciónRESUMEN
PURPOSE: Glibenclamide (Gb) is used in type II diabetes mellitus but also in the last 10 years, off label, in patients with neonatal syndromic hyperglycemia carrying a mutation of Kir6.2 or SUR1. No studies have reported Gb pharmacokinetics in children. In this study, oral Gb pharmacokinetics was investigated in children in order to describe the concentration time courses, the influence of covariates, and the relationships between drug concentrations and efficacy. METHODS: Gb concentrations were measured in 18 children after the switch from subcutaneous insulin to oral tablets of Gb (crushed tablets for 33 % of patients). A total of 229 plasma Gb concentrations and 187 blood glucose measurements were available. A population model was developed with NONMEM. RESULTS: Body weight was the most significant parameter on clearance and explained a substantial part of the variability. A variant genotype of CYP2C9 (i.e., *1/*2 and *1/*3) explained also a part of the remaining variability on Gb clearance. Patients carrying these allelic variants had a clearance decreased by 45 %. A link between daily area under the curve (AUC0-24 h) and metabolic control diabetes was found. CONCLUSIONS: This study evaluates for the first time the pharmacokinetics of oral Gb in children and constitutes a first step towards dose individualization of this drug in a particularly vulnerable population.
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Gliburida/farmacocinética , Hipoglucemiantes/farmacocinética , Modelos Biológicos , Administración Oral , Glucemia/análisis , Niño , Preescolar , Citocromo P-450 CYP2C9/genética , Relación Dosis-Respuesta a Droga , Genotipo , Gliburida/administración & dosificación , Gliburida/sangre , Gliburida/uso terapéutico , Humanos , Hiperglucemia/sangre , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/genética , Hiperglucemia/metabolismo , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/sangre , Hipoglucemiantes/uso terapéutico , Inyecciones Subcutáneas , Insulina/administración & dosificación , Insulina/uso terapéutico , Mutación , Uso Fuera de lo Indicado , Canales de Potasio de Rectificación Interna/genética , Receptores de Sulfonilureas/genética , Síndrome , ComprimidosRESUMEN
Glyburide, a sulfonylurea drug used to treat type 2 diabetes, boasts neuroprotective effects by targeting the sulfonylurea receptor 1 (SUR1) and associated ion channels in various cell types, including those in the central nervous system and the retina. Previously, we demonstrated that glyburide therapy improved retinal function and structure in a rat model of diabetic retinopathy. In the present study, we explore the application of glyburide in non-neovascular ("dry") age-related macular degeneration (AMD), another progressive disease characterized by oxidative stress-induced damage and neuroinflammation that trigger cell death in the retina. We show that glyburide administration to a human cone cell line confers protection against oxidative stress, inflammasome activation, and apoptosis. To corroborate our in vitro results, we also conducted a case-control study, controlling for AMD risk factors and other diabetes medications. It showed that glyburide use in patients reduces the odds of new-onset dry AMD. A positive dose-response relationship is observed from this analysis, in which higher cumulative doses of glyburide further reduce the odds of new-onset dry AMD. In the quest for novel therapies for AMD, glyburide emerges as a promising repurposable drug given its known safety profile. The results from this study provide insights into the multifaceted actions of glyburide and its potential as a neuroprotective agent for retinal diseases; however, further preclinical and clinical studies are needed to validate its therapeutic potential in the context of degenerative retinal disorders such as AMD.
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Photoreceptors and retinal pigment epithelial cells (RPE) targeting remains challenging in ocular gene therapy. Viral gene transfer, the only method having reached clinical evaluation, still raises safety concerns when administered via subretinal injections. We have developed a novel transfection method in the adult rat, called suprachoroidal electrotransfer (ET), combining the administration of nonviral plasmid DNA into the suprachoroidal space with the application of an electrical field. Optimization of injection, electrical parameters and external electrodes geometry using a reporter plasmid, resulted in a large area of transfected tissues. Not only choroidal cells but also RPE, and potentially photoreceptors, were efficiently transduced for at least a month when using a cytomegalovirus (CMV) promoter. No ocular complications were recorded by angiographic, electroretinographic, and histological analyses, demonstrating that under selected conditions the procedure is devoid of side effects on the retina or the vasculature integrity. Moreover, a significant inhibition of laser induced-choroidal neovascularization (CNV) was achieved 15 days after transfection of a soluble vascular endothelial growth factor receptor-1 (sFlt-1)-encoding plasmid. This is the first nonviral gene transfer technique that is efficient for RPE targeting without inducing retinal detachment. This novel minimally invasive nonviral gene therapy method may open new prospects for human retinal therapies.
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Coroides/metabolismo , Técnicas de Transferencia de Gen , Retina/metabolismo , Transfección/métodos , Animales , Femenino , Masculino , RatasRESUMEN
Early treatment of neonatal diabetes with sulfonylureas has been proven to produce marked improvements of neurodevelopment, beside the demonstrated efficacy on glycemic control. Several barriers still prevent an early treatment in preterm babies including the limited availability of suitable galenic form of glibenclamide. We adopted oral glibenclamide suspension (Amglidia) for the early treatment of neonatal diabetes due to an homozygous variant of KCNJ11 gene c.10C>T [p.Arg4Cys] in an extremely preterm infant born at 26 + 2 weeks' of gestational age. After ~6 weeks of insulin treatment with a low glucose intake (4.5 g/kg/day), the infant was switched to Amglidia 6 mg/ml diluted in maternal milk, via nasogastric tube (0.2 mg/kg/day) progressively reduced to 0.01 mg/kg/day (after ~3 months). While on glibenclamide, the patient exhibited a mean daily growth of 11 g/kg/day. The treatment was suspended at month 6 of birth (weight 4.9 kg [5th-10th centile], M3 of c.a.) for normalization of glucose profile. During the treatment, the patient exhibited a stable glucose profile within the range of 4-8 mmol/L in the absence of hypo or hyperglycemic episodes with 2-3 blood glucose tests per day. The patient was diagnosed with retinopathy of prematurity Stade II in Zone II without plus disease at 32 weeks, with progressive regression and complete retinal vascularization at 6 months of birth. Amglidia could be regarded as the specific treatment for neonatal diabetes even in preterm babies due to its beneficial effect on the metabolic and neurodevelopmental side.
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Herpes simplex ocular infection is a major cause of corneal blindness. Local antiviral treatments exist but are associated with corneal toxicity, and resistance has become an issue. We evaluated the biodistribution and efficacy of a humanized anti-herpes simplex virus (anti-HSV) IgG FAb fragment (AC-8; 53 kDa) following repeated topical administration. AC-8 was found in the corneal epithelium, anterior stroma, subepithelial stromal cells, and retinal glial cells, with preferential entry through the ocular limbus. AC-8 was active against 13 different strains of HSV-1, with 50% and 90% mean effective concentrations (MEC(50) and MEC(90), respectively) ranging from 0.03 to 0.13 µg/ml, indicating broad-spectrum activity. The in vivo efficacy of AC-8 was evaluated in a mouse model of herpes-induced ocular disease. Treatment with low-dose AC-8 (1 mg/ml) slightly reduced the ocular disease scores. A greater reduction of the disease scores was observed in the 10-mg/ml AC-8-treated group, but not as much as with trifluridine (TFT). AC-8 treatment reduced viral titers but less than trifluridine. AC-8 did not display any toxicity to the cornea or other structures in the eye. In summary, topical instillation of an anti-HSV FAb can be used on both intact and ulcerated corneas. It is well tolerated and does not alter reepithelialization. Further studies to improve the antiviral effect are needed for AC-8 to be considered for therapeutic use.
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Anticuerpos Monoclonales Humanizados/farmacocinética , Antivirales/farmacocinética , Ojo/metabolismo , Herpesvirus Humano 1/inmunología , Fragmentos Fab de Inmunoglobulinas/metabolismo , Queratitis Herpética/virología , Administración Tópica , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Antivirales/inmunología , Antivirales/administración & dosificación , Antivirales/inmunología , Farmacorresistencia Viral , Epitelio Corneal/metabolismo , Ojo/efectos de los fármacos , Ojo/virología , Humanos , Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Fragmentos Fab de Inmunoglobulinas/inmunología , Concentración 50 Inhibidora , Queratitis Herpética/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Neuroglía/metabolismo , Ratas , Retina/metabolismo , Células del Estroma/metabolismo , Distribución Tisular , Trifluridina/administración & dosificaciónRESUMEN
Ursodeoxycholic (UDCA) and tauroursodeoxycholic (TUDCA) acids have shown neuroprotective properties in neurodegenerative diseases, but differential effects of the two bile acids have been poorly explored. The aim of this study was to evaluate the neuroprotective effects of UDCA versus TUDCA in a neuroretinal degeneration model and to compare transcriptionally regulated pathways. The WERI-Rb-1 human cone-like cell line and retinal explants were exposed to albumin and TUDCA or UDCA. Viability, cell death, and microglial activation were quantified. Transcriptionally regulated pathways were analyzed after RNA sequencing using the edgeR bioconductor package. Pre-treatment of cone-like cells with UDCA or TUDCA significantly protected cells from albumin toxicity. On retinal explants, either bile acid reduced apoptosis, necroptosis, and microglia activation at 6 h. TUDCA induced the regulation of 463 genes, whilst 31 genes were regulated by UDCA. Only nineteen common genes were regulated by both bile acids, mainly involved in iron control, cell death, oxidative stress, and cell metabolism. As compared to UDCA, TUDCA up-regulated genes involved in endoplasmic reticulum stress pathways and down-regulated genes involved in axonal and neuronal development. Either bile acid protected against albumin-induced cell loss. However, TUDCA regulated substantially more neuroprotective genes than UDCA.
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Diabetic retinopathy (DR) remains a major cause of vision loss, due to macular edema, retinal ischemia and death of retinal neurons. We previously demonstrated that acute administration of glibenclamide into the vitreous, or given orally at a non-hypoglycemic dose, protected the structure and the function of the retina in three animal models that each mimic aspects of diabetic retinopathy in humans. In this pilot study, we investigated whether one year of chronic oral glibenclamide, in a non-hypoglycemic regimen (Amglidia®, 0.4 mg/kg, Ammtek/Nordic Pharma, 5 d/week), could alleviate the retinopathy that develops in the Goto-Kakizaki (GK) rat. In vivo, retinal function was assessed by electroretinography (ERG), retinal thickness by optical coherence tomography (OCT) and retinal perfusion by fluorescein and indocyanin green angiographies. The integrity of the retinal pigment epithelium (RPE) that constitutes the outer retinal barrier was evaluated by quantitative analysis of the RPE morphology on flat-mounted fundus ex vivo. Oral glibenclamide did not significantly reduce the Hb1Ac levels but still improved retinal function, as witnessed by the reduction in scotopic implicit times, limited diabetes-induced neuroretinal thickening and the extension of ischemic areas, and it improved the capillary coverage. These results indicate that low doses of oral glibenclamide could still be beneficial for the prevention of type 2 diabetic retinopathy. Whether the retinas ofpatients treated specifically with glibenclamideare less at risk of developing diabetic complications remains to be demonstrated.
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Rho-associated kinase (ROCK) activation was shown to contribute to microvascular closure, retinal hypoxia, and to retinal pigment epithelium (RPE) barrier disruption in a rat model of diabetic retinopathy. Fasudil, a clinically approved ROCK inhibitor, improved retinal perfusion and reduced edema in this model, indicating that ROCK inhibition could be a promising new therapeutic approach for the treatment of diabetic retinopathy. However, due to its short intravitreal half-life, fasudil is not suitable for long-term treatment. In this study, we evaluated a very potent ROCK1/2 inhibitor (BIRKI) in a depot formulation administered as a single intravitreal injection providing a slow release for at least four weeks. Following BIRKI intravitreal injection in old Goto-Kakizaki (GK) type 2 diabetic rats, we observed a significant reduction in ROCK1 activity in the retinal pigment epithelium/choroid complex after 8 days and relocation of ROCK1 to the cytoplasm and nucleus in retinal pigment epithelium cells after 28 days. The chronic ROCK inhibition by the BIRKI depot formulation restored retinal pigment epithelial cell morphology and distribution, favored retinal capillaries dilation, and reduced hypoxia and inner blood barrier leakage observed in the diabetic retina. No functional or morphological negative effects were observed, indicating suitable tolerability of BIRKI after intravitreous injection. In conclusion, our data suggest that sustained ROCK inhibition, provided by BIRKI slow-release formulation, could be a valuable treatment option for diabetic retinopathy, especially with regard to the improvement of retinal vascular infusion and protection of the outer retinal barrier.
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Diabetic retinopathy remains a major cause of vision loss worldwide. Mineralocorticoid receptor (MR) pathway activation contributes to diabetic nephropathy, but its role in retinopathy is unknown. In this study, we show that MR is overexpressed in the retina of type 2 diabetic Goto-Kakizaki (GK) rats and humans and that cortisol is the MR ligand in human eyes. Lipocalin 2 and galectin 3, two biomarkers of diabetes complications regulated by MR, are increased in GK and human retina. The sustained intraocular delivery of spironolactone, a steroidal mineralocorticoid antagonist, decreased the early and late pathogenic features of retinopathy in GK rats, such as retinal inflammation, vascular leakage, and retinal edema, through the upregulation of genes encoding proteins known to intervene in vascular permeability such as Hey1, Vldlr, Pten, Slc7a1, Tjp1, Dlg1, and Sesn2 but did not decrease VEGF. Spironolactone also normalized the distribution of ion and water channels in macroglial cells. These results indicate that MR is activated in GK and human diabetic retina and that local MR antagonism could be a novel therapeutic option for diabetic retinopathy.
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Diabetes Mellitus Tipo 2/metabolismo , Retinopatía Diabética/etiología , Receptores de Mineralocorticoides/metabolismo , Retina/patología , Neuronas Retinianas/patología , Espironolactona/farmacología , Animales , Preparaciones de Acción Retardada , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hidrocortisona/metabolismo , Masculino , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Antagonistas de Receptores de Mineralocorticoides/química , Antagonistas de Receptores de Mineralocorticoides/farmacología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Ratas , Ratas Endogámicas , Receptores de Mineralocorticoides/genética , Neuronas Retinianas/efectos de los fármacos , Espironolactona/administración & dosificación , Espironolactona/química , Regulación hacia Arriba , Cuerpo VítreoRESUMEN
Rhegmatogenous retinal detachment (RD) is a threatening visual condition and a human disease model for retinal degenerations. Despite successful reattachment surgery, vision does not fully recover, due to subretinal fluid accumulation and subsequent photoreceptor cell death, through mechanisms that recapitulate those of retinal degenerative diseases. Hydrophilic bile acids are neuroprotective in animal models, but whether they can be used orally for retinal diseases is unknown. Ursodeoxycholic acid (UDCA) being approved for clinical use (e.g., in cholestasis), we have evaluated the ocular bioavailability of oral UDCA, administered to patients before RD surgery. The level of UDCA in ocular media correlated with the extent of blood retinal barrier disruption, evaluated by the extent of detachment and the albumin concentration in subretinal fluid. UDCA, at levels measured in ocular media, protected photoreceptors from apoptosis and necrosis in rat retinal explants, an ex vivo model of RD. The subretinal fluid from UDCA-treated patients, collected during surgery, significantly protected rat retinal explants from cell death, when compared to subretinal fluid from control patients. Pan-transcriptomic analysis of the retina showed that UDCA upregulated anti-apoptotic, anti-oxidant, and anti-inflammatory genes. Oral UDCA is a potential neuroprotective adjuvant therapy in RD and other retinal degenerative diseases and should be further evaluated in a clinical trial.
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Apoptosis/efectos de los fármacos , Barrera Hematorretinal/metabolismo , Colagogos y Coleréticos/farmacología , Retina/efectos de los fármacos , Células Fotorreceptoras Retinianas Conos/efectos de los fármacos , Degeneración Retiniana/terapia , Desprendimiento de Retina/terapia , Ácido Ursodesoxicólico/farmacología , Administración Oral , Albúminas/metabolismo , Animales , Disponibilidad Biológica , Línea Celular , Colagogos y Coleréticos/metabolismo , Criocirugía , Femenino , Humanos , Técnicas In Vitro , Terapia por Láser , Masculino , Persona de Mediana Edad , Necrosis , Células Fotorreceptoras de Vertebrados/efectos de los fármacos , Células Fotorreceptoras de Vertebrados/patología , Ratas , Retina/patología , Retina/cirugía , Células Fotorreceptoras Retinianas Conos/patología , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Desprendimiento de Retina/metabolismo , Desprendimiento de Retina/patología , Líquido Subretiniano/química , Ácido Ursodesoxicólico/metabolismo , VitrectomíaRESUMEN
Sulfonylureas, widely used as hypoglycemic agents in adults with type 2 diabetes, have neuroprotective effects in preclinical models of central nervous system injury, and in children with neuropsychomotor impairments linked to neonatal diabetes secondary to ATP-sensitive potassium channel mutations. In the human and rodent retina, we show that the glibenclamide-activated channel sulfonylurea receptor 1 (SUR1) is expressed in the retina and enriched in the macula; we also show that it colocalizes with the potassium channel Kir6.2, and with the cation channel transporter TRPM4. Glibenclamide (glyburide), administered at doses that did not decrease the glycemia, or injected directly into the eye, protected the structure and the function of the retina in various models of retinal injury that recapitulate the pathogenic neurodegenerative events in the diabetic retina. The downregulation of SUR1 using a siRNA suppressed the neuroprotective effects of glibenclamide on excitotoxic stress-induced cell death. The glibenclamide effects include the transcriptional regulation of antioxidant and neuroprotective genes. Ocular glibenclamide could be repurposed for diabetic retinopathy.
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Gliburida/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedades de la Retina/tratamiento farmacológico , Neuronas Retinianas/efectos de los fármacos , Administración Oral , Animales , Chlorocebus aethiops , Diabetes Mellitus Experimental/patología , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/genética , Retinopatía Diabética/patología , Femenino , Gliburida/administración & dosificación , Humanos , Hiperglucemia/metabolismo , Hipoglucemiantes/farmacología , Macaca fascicularis , Masculino , Persona de Mediana Edad , Fármacos Neuroprotectores/administración & dosificación , Canales de Potasio de Rectificación Interna/metabolismo , Ratas Endogámicas Lew , Ratas Wistar , Enfermedades de la Retina/etiología , Enfermedades de la Retina/patología , Neuronas Retinianas/patología , Receptores de Sulfonilureas/metabolismo , Canales Catiónicos TRPM/metabolismoRESUMEN
The eyes and the gaze participate in a major way in our non-verbal language, even before the verb appeared. From the Bible to contemporary language, through Greek mythology, theater, literature or spoken language, a multitude of expressions and proverbs present the eye, what it sees and what it symbolizes.
TITLE: Des yeux et du regard : proverbes et expressions. ABSTRACT: Les yeux et le regard participent de façon majeure à notre langage non verbal, avant même l'apparition du verbe. Depuis la Bible jusqu'au langage contemporain, en passant par la mythologie grecque, le théâtre, la littérature ou le langage parlé, une multitude d'expressions et de proverbes mettent en scène l'Åil, ce qu'il voit et ce qu'il symbolise. Cet article parcourt les champs sémantiques de l'Åil et du regard, leur évolution dans le temps, et leur étonnante richesse. En définitive, une revue de notre humanité.
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Aforismos y Proverbios como Asunto , Expresión Facial , Fijación Ocular/fisiología , Fenómenos Fisiológicos Oculares , Cultura , Ojo , Humanos , Relaciones Metafisicas Mente-Cuerpo/fisiología , Mitología , Observación , Prejuicio/psicología , Religión y Psicología , Supersticiones , Visión Ocular/fisiologíaRESUMEN
Neonatal Diabetes (ND) mellitus is a rare genetic disease (1 in 90,000 live births). It is defined by the presence of severe hyperglycaemia associated with insufficient or no circulating insulin, occurring mainly before 6 months of age and rarely between 6 months and 1 year. Such hyperglycaemia requires either transient treatment with insulin in about half of cases, or permanent insulin treatment. The disease is explained by two major groups of mechanism: malformation of the pancreas with altered insulin-secreting cells development/survival or abnormal function of the existing pancreatic ß cell. The most frequent genetic causes of neonatal diabetes mellitus with abnormal ß cell function are abnormalities of the 6q24 locus and mutations of the ABCC8 or KCNJ11 genes coding for the potassium channel in the pancreatic ß cell. Other genes are associated with pancreas malformation or insufficient ß cells development or destruction of ß cells. Clinically, compared to patients with an ABCC8 or KCNJ11 mutation, patients with a 6q24 abnormality have lower birth weight and height, are younger at diagnosis and remission, and have a higher malformation frequency. Patients with an ABCC8 or KCNJ11 mutation have neurological and neuropsychological disorders in all those tested carefully. Up to 86% of patients who go into remission have recurrent diabetes when they reach puberty, with no difference due to the genetic origin. All these results reinforce the importance of prolonged follow-up by a multidisciplinary pediatric team, and later doctors specializing in adult medicine. 90% of the patients with an ABCC8 or KCNJ11 mutation as well as those with 6q24 anomalies are amenable to a successful switch from insulin injection to oral sulfonylureas.
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PURPOSE: This study investigates the effects of triamcinolone acetonide (TA) on retinal endothelial cells in vitro and explores the potential vascular toxic effect of TA injected into the vitreous cavity of rats in vivo. METHODS: Subconfluent endothelial cells were treated with either 0.1 mg/ml or 1 mg/ml TA in 1% ethanol. Control cells were either untreated or exposed to 1% ethanol. Cell viability was evaluated at 24 h, 72 h, and five days using the tetrazolium 3-(4,5-dimethylthiazol-2-yl)-2,5 phenyltetrazolium bromide test (MTT) and lactate dehydrogenase (LDH) assays. Cell proliferation was evaluated by 5-bromo-2-deoxyuridine (BrdU) test. Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling assay (TUNEL assay), annexin-binding, and caspase 3 activation. Caspase-independent cell deaths were investigated by immunohistochemistry using antibodies against apoptosis inducing factor (AIF), cytochrome C, microtubule-associated protein (MAP)-light chain 3 (MAP-LC3), and Leukocyte Elastase Inhibitor/Leukocyte Elastase Inhibitor-derived DNase II (LEI/L-DNase II). In vivo, semithin and ultrathin structure analysis and vascular casts were performed to examine TA-induced changes of the choroidal vasculature. In addition, outer segments phagocytosis assay on primary retinal pigment epithelium (RPE) cells was performed to assess cyclooxygenase (COX-2) and vascular endothelial growth factor (VEGF) mRNAs upregulation with or without TA. RESULTS: The inhibitory effect of TA on cell proliferation could not explain the significant reduction in cell viability. Indeed, TA induced a time-dependent reduction of bovine retinal endothelial cells viability. Annexin-binding positive cells were observed. Cytochrome C was not released from mitochondria. L-DNase II was found translocated to the nucleus, meaning that LEI was changed into L-DNase II. AIF was found nuclearized in some cells. LC3 labeling showed the absence of autophagic vesicles. No autophagy or caspase dependent apoptosis was identified. At 1 mg/ml TA induced necrosis while exposure to lower concentrations for 3 to 5 days induced caspase independent apoptosis involving AIF and LEI/L-DNase II. In vivo, semithin and ultrathin structure analysis and vascular casts revealed that TA mostly affected the choroidal vasculature with a reduction of choroidal thickness and increased the avascular areas of the choriocapillaries. Experiments performed on primary RPE cells showed that TA downregulates the basal expression of COX-2 and VEGF and inhibits the outer segments (OS)-dependent COX-2 induction but not the OS-dependent VEGF induction. CONCLUSIONS: This study demonstrates for the first time that glucocorticoids exert direct toxic effect on endothelial cells through caspase-independent cell death mechanisms. The choroidal changes observed after TA intravitreous injection may have important implications regarding the safety profile of TA use in human eyes.
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Ojo/irrigación sanguínea , Ojo/efectos de los fármacos , Triamcinolona Acetonida/toxicidad , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Caspasas/metabolismo , Bovinos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Coroides/irrigación sanguínea , Coroides/efectos de los fármacos , Molde por Corrosión , Ciclooxigenasa 2/metabolismo , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/enzimología , Ojo/anatomía & histología , Ojo/ultraestructura , Fagocitosis/efectos de los fármacos , Ratas , Retina/citología , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
PURPOSE: To evaluate the photodynamic potential of a new hydrosoluble photosensitizer (WST-11, Stakel; Steba Biotech, Toussus-Le-Noble, France), for use in occlusion of normal choroidal vessels in the rabbit eye and CNV (choroidal neovascularization) in the rat eye. METHODS: Occlusive and nonocclusive parameters of Stakel and verteporfin photodynamic therapy (PDT) were investigated in pigmented rabbits. Eyes were followed by fluorescein angiography (FA) and histology at various intervals after PDT. RESULTS: When occlusive parameters (fluence of 50 J/cm(2), 5 mg/kg drug dose and DLI [distance to light illumination] of 1 minute) were used, Stakel PDT was efficient immediately after treatment without associated structural damage of the RPE and retina overlying the treated choroid in the rabbit eye. Two days later, total occlusion of the choriocapillaries was seen in 100% of the treated eyes, along with accompanying histologic structural changes in the overlying retina. When the occlusive parameters (fluence, 100 J/cm2; drug dose, 12 mg/m2; and DLI, 5 minutes) of verteporfin PDT were used, occlusion of the choriocapillaries was observed in 89% of the treated eyes. Histology performed immediately after treatment demonstrated structural damage of the overlying retina and RPE layer. Weaker, nonocclusive Stakel PDT parameters (25 J/cm2, 5 mg/kg, and DLI of 10 minutes) did not induce choriocapillary occlusion or retinal lesions on FA or histology. Weaker, nonocclusive verteporfin PDT parameters (10 J/cm2, 0.2 mg/kg, and DLI of 5 minutes) did not induce choriocapillary occlusion. However, histology of these eyes showed the presence of damage in the retinal and choroidal tissues. Moreover, preliminary results indicate that selective CNV occlusion can be achieved with Stakel PDT in the rat eye. CONCLUSIONS: Unlike verteporfin PDT, Stakel PDT does not cause direct damage to the RPE cell layer or retina. These observations indicate that Stakel PDT may have a high potential for beneficial therapeutic outcomes in treatment of AMD.
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Bacterioclorofilas/uso terapéutico , Neovascularización Coroidal/tratamiento farmacológico , Modelos Animales de Enfermedad , Fotoquimioterapia , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Bacterioclorofilas/farmacocinética , Bacterioclorofilas/toxicidad , Coroides/efectos de los fármacos , Neovascularización Coroidal/etiología , Neovascularización Coroidal/patología , Evaluación Preclínica de Medicamentos , Angiografía con Fluoresceína , Coagulación con Láser , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/toxicidad , Epitelio Pigmentado Ocular/efectos de los fármacos , Epitelio Pigmentado Ocular/ultraestructura , Porfirinas/uso terapéutico , Conejos , Ratas , Ratas Endogámicas BN , Retina/efectos de los fármacos , Retina/ultraestructura , VerteporfinaRESUMEN
Macular edema consists of intra- or subretinal fluid accumulation in the macular region. It occurs during the course of numerous retinal disorders and can cause severe impairment of central vision. Major causes of macular edema include diabetes, branch and central retinal vein occlusion, choroidal neovascularization, posterior uveitis, postoperative inflammation and central serous chorioretinopathy. The healthy retina is maintained in a relatively dehydrated, transparent state compatible with optimal light transmission by multiple active and passive systems. Fluid accumulation results from an imbalance between processes governing fluid entry and exit, and is driven by Starling equation when inner or outer blood-retinal barriers are disrupted. The multiple and intricate mechanisms involved in retinal hydro-ionic homeostasis, their molecular and cellular basis, and how their deregulation lead to retinal edema, are addressed in this review. Analyzing the distribution of junction proteins and water channels in the human macula, several hypotheses are raised to explain why edema forms specifically in the macular region. "Pure" clinical phenotypes of macular edema, that result presumably from a single causative mechanism, are detailed. Finally, diabetic macular edema is investigated, as a complex multifactorial pathogenic example. This comprehensive review on the current understanding of macular edema and its mechanisms opens perspectives to identify new preventive and therapeutic strategies for this sight-threatening condition.