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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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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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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 , Doenças do Recém-Nascido , Canais de Potássio Corretores do Fluxo de Internalização , Adulto , Criança , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética , Epilepsia/genética , Glibureto , Humanos , Recém-Nascido , Doenças do Recém-Nascido/tratamento farmacológico , Doenças do Recém-Nascido/genética , Canais KATP/genética , Hipotonia Muscular , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Compostos de Sulfonilureia/uso terapêutico , Receptores de Sulfonilureias/genéticaRESUMO
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 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 , Retinopatia Diabética/etiologia , Receptores de Mineralocorticoides/metabolismo , Retina/patologia , Neurônios Retinianos/patologia , Espironolactona/farmacologia , Animais , Preparações de Ação Retardada , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hidrocortisona/metabolismo , Masculino , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/química , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ratos , Ratos Endogâmicos , Receptores de Mineralocorticoides/genética , Neurônios Retinianos/efeitos dos fármacos , Espironolactona/administração & dosagem , Espironolactona/química , Regulação para Cima , Corpo VítreoRESUMO
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 (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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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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Apoptose/efeitos dos fármacos , Barreira Hematorretiniana/metabolismo , Colagogos e Coleréticos/farmacologia , Retina/efeitos dos fármacos , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Degeneração Retiniana/terapia , Descolamento Retiniano/terapia , Ácido Ursodesoxicólico/farmacologia , Administração Oral , Albuminas/metabolismo , Animais , Disponibilidade Biológica , Linhagem Celular , Colagogos e Coleréticos/metabolismo , Criocirurgia , Feminino , Humanos , Técnicas In Vitro , Terapia a Laser , Masculino , Pessoa de Meia-Idade , Necrose , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Células Fotorreceptoras de Vertebrados/patologia , Ratos , Retina/patologia , Retina/cirurgia , Células Fotorreceptoras Retinianas Cones/patologia , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia , Descolamento Retiniano/metabolismo , Descolamento Retiniano/patologia , Líquido Sub-Retiniano/química , Ácido Ursodesoxicólico/metabolismo , VitrectomiaRESUMO
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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Glibureto/farmacologia , Fármacos Neuroprotetores/farmacologia , Doenças Retinianas/tratamento farmacológico , Neurônios Retinianos/efeitos dos fármacos , Administração Oral , Animais , Chlorocebus aethiops , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/genética , Retinopatia Diabética/patologia , Feminino , Glibureto/administração & dosagem , Humanos , Hiperglicemia/metabolismo , Hipoglicemiantes/farmacologia , Macaca fascicularis , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/administração & dosagem , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Ratos Endogâmicos Lew , Ratos Wistar , Doenças Retinianas/etiologia , Doenças Retinianas/patologia , Neurônios Retinianos/patologia , Receptores de Sulfonilureias/metabolismo , Canais de Cátion TRPM/metabolismoRESUMO
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 e Provérbios como Assunto , Expressão Facial , Fixação Ocular/fisiologia , Fenômenos Fisiológicos Oculares , Cultura , Olho , Humanos , Relações Metafísicas Mente-Corpo/fisiologia , Mitologia , Observação , Preconceito/psicologia , Religião e Psicologia , Superstições , Visão Ocular/fisiologiaRESUMO
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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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/congênito , Diabetes Mellitus/tratamento farmacológico , Glibureto/administração & dosagem , Hipoglicemiantes/administração & dosagem , Doenças do Recém-Nascido/tratamento farmacológico , Administração Oral , Adolescente , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Criança , Pré-Escolar , Feminino , Glibureto/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Lactente , Recém-Nascido , Masculino , Aceitação pelo Paciente de Cuidados de Saúde , Suspensões , Comprimidos , Resultado do TratamentoRESUMO
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.
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Edema Macular/fisiopatologia , Barreira Hematorretiniana , Coriorretinopatia Serosa Central/complicações , Coriorretinopatia Serosa Central/fisiopatologia , Neovascularização de Coroide/complicações , Neovascularização de Coroide/fisiopatologia , Retinopatia Diabética/complicações , Retinopatia Diabética/fisiopatologia , Angiofluoresceinografia , Humanos , Edema Macular/diagnóstico , Edema Macular/prevenção & controle , Oclusão da Veia Retiniana/complicações , Oclusão da Veia Retiniana/fisiopatologia , Vasos Retinianos/fisiopatologia , Líquido Sub-Retiniano , Tomografia de Coerência ÓpticaRESUMO
Mineralocorticoid receptor (MR) contributes to retinal/choroidal homeostasis. Excess MR activation has been shown to be involved in pathogenesis of central serous chorioretinopathy (CSCR). Systemic administration of MR antagonist (MRA) reduces subretinal fluid and choroidal vasodilation, and improves the visual acuity in CSCR patients. To achieve long term beneficial effects in the eye while avoiding systemic side-effects, we propose the use of biodegradable spironolactone-loaded poly-lactic-co-glycolic acid (PLGA) microspheres (MSs). In this work we have evaluated the ocular tolerance of MSs containing spironolactone in rat' eyes. As previous step, we have also studied the tolerance of the commercial solution of canrenoate salt, active metabolite of spironolactone. PLGA MSs allowed in vitro sustained release of spironolactone for 30days. Rat eyes injected with high intravitreous concentration of PLGA MSs (10mg/mL) unloaded and loaded with spironolactone maintained intact retinal lamination at 1month. However enhanced glial fibrillary acidic protein immunostaining and activated microglia/macrophages witness retinal stress were observed. ERG also showed impaired photoreceptor function. Intravitreous PLGA MSs concentration of 2mg/mL unloaded and loaded with spironolactone resulted well tolerated. We observed reduced microglial/macrophage activation in rat retina compared to high concentration of MSs with normal retinal function according to ERG. Spironolactone released from low concentration of MSs was active in the rat retina. Low concentration of spironolactone-loaded PLGA MSs could be a safe therapeutic choice for chorioretinal disorders in which illicit MR activation could be pathogenic.
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Ácido Láctico/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Ácido Poliglicólico/administração & dosagem , Espironolactona/administração & dosagem , Animais , Ácido Canrenoico/administração & dosagem , Corpo Ciliar/anatomia & histologia , Corpo Ciliar/efeitos dos fármacos , Liberação Controlada de Fármacos , Injeções Intravítreas , Ácido Láctico/química , Macrófagos/efeitos dos fármacos , Masculino , Microglia/efeitos dos fármacos , Microesferas , Antagonistas de Receptores de Mineralocorticoides/química , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos Wistar , Retina/anatomia & histologia , Retina/efeitos dos fármacos , Retina/fisiologia , Espironolactona/química , Espironolactona/farmacocinéticaRESUMO
In diabetic retinopathy, the exact mechanisms leading to retinal capillary closure and to retinal barriers breakdown remain imperfectly understood. Rho-associated kinase (ROCK), an effector of the small GTPase Rho, involved in cytoskeleton dynamic regulation and cell polarity is activated by hyperglycemia. In one year-old Goto Kakizaki (GK) type 2 diabetic rats retina, ROCK-1 activation was assessed by its cellular distribution and by phosphorylation of its substrates, MYPT1 and MLC. In both GK rat and in human type 2 diabetic retinas, ROCK-1 is activated and associated with non-apoptotic membrane blebbing in retinal vessels and in retinal pigment epithelium (RPE) that respectively form the inner and the outer barriers. Activation of ROCK-1 induces focal vascular constrictions, endoluminal blebbing and subsequent retinal hypoxia. In RPE cells, actin cytoskeleton remodeling and membrane blebs in RPE cells contributes to outer barrier breakdown. Intraocular injection of fasudil, significantly reduces both retinal hypoxia and RPE barrier breakdown. Diabetes-induced cell blebbing may contribute to ischemic maculopathy and represent an intervention target.
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Retinopatia Diabética/metabolismo , Células Endoteliais/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Quinases Associadas a rho/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Idoso , Animais , Biomarcadores , Estudos de Casos e Controles , Citoesqueleto/metabolismo , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/etiologia , Retinopatia Diabética/patologia , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/ultraestrutura , Feminino , Imunofluorescência , Humanos , Hipóxia/metabolismo , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Ratos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/patologia , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Vasos Retinianos/ultraestrutura , Quinases Associadas a rho/genéticaRESUMO
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.
Assuntos
Neurotoxinas/toxicidade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacologia , Ativador de Plasminogênio Tecidual/efeitos adversos , Ativador de Plasminogênio Tecidual/farmacologia , Animais , Apoptose/efeitos dos fármacos , Eletrorretinografia , Injeções Intravítreas , Masculino , Ratos Long-Evans , Proteínas Recombinantes/administração & dosagem , Retina , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Ativador de Plasminogênio Tecidual/administração & dosagemRESUMO
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.
Assuntos
Glibureto/farmacocinética , Hipoglicemiantes/farmacocinética , Modelos Biológicos , Administração Oral , Glicemia/análise , Criança , Pré-Escolar , Citocromo P-450 CYP2C9/genética , Relação Dose-Resposta a Droga , Genótipo , Glibureto/administração & dosagem , Glibureto/sangue , Glibureto/uso terapêutico , Humanos , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Hipoglicemiantes/uso terapêutico , Injeções Subcutâneas , Insulina/administração & dosagem , Insulina/uso terapêutico , Mutação , Uso Off-Label , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores de Sulfonilureias/genética , Síndrome , ComprimidosRESUMO
Iron is essential for retinal function but contributes to oxidative stress-mediated degeneration. Iron retinal homeostasis is highly regulated and transferrin (Tf), a potent iron chelator, is endogenously secreted by retinal cells. In this study, therapeutic potential of a local Tf delivery was evaluated in animal models of retinal degeneration. After intravitreal injection, Tf spread rapidly within the retina and accumulated in photoreceptors and retinal pigment epithelium, before reaching the blood circulation. Tf injected in the vitreous prior and, to a lesser extent, after light-induced retinal degeneration, efficiently protected the retina histology and function. We found an association between Tf treatment and the modulation of iron homeostasis resulting in a decrease of iron content and oxidative stress marker. The immunomodulation function of Tf could be seen through a reduction in macrophage/microglial activation as well as modulated inflammation responses. In a mouse model of hemochromatosis, Tf had the capacity to clear abnormal iron accumulation from retinas. And in the slow P23H rat model of retinal degeneration, a sustained release of Tf in the vitreous via non-viral gene therapy efficently slowed-down the photoreceptors death and preserved their function. These results clearly demonstrate the synergistic neuroprotective roles of Tf against retinal degeneration and allow identify Tf as an innovative and not toxic therapy for retinal diseases associated with oxidative stress.
Assuntos
Modelos Animais de Doenças , Inflamação/prevenção & controle , Ferro/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Degeneração Retiniana/prevenção & controle , Transferrina/farmacologia , Animais , Células Cultivadas , Homeostase/efeitos dos fármacos , Técnicas Imunoenzimáticas , Inflamação/induzido quimicamente , Masculino , Camundongos , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Degeneração Retiniana/induzido quimicamente , Degeneração Retiniana/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: Neonatal diabetes secondary to mutations in potassium-channel subunits is a rare disease but constitutes a paradigm for personalized genetics-based medicine, as replacing the historical treatment with insulin injections with oral sulfonylurea (SU) therapy has been proven beneficial. SU receptors are widely expressed in the brain, and we therefore evaluated potential effects of SU on neurodevelopmental parameters, which are known to be unresponsive to insulin. RESEARCH DESIGN AND METHODS: We conducted a prospective single-center study. Nineteen patients (15 boys aged 0.1-18.5 years) were switched from insulin to SU therapy. MRI was performed at baseline. Before and 6 or 12 months after the switch, patients underwent quantitative neurological and developmental assessments and electrophysiological nerve and muscle testing. RESULTS: At baseline, hypotonia, deficiencies in gesture conception or realization, and attention disorders were common. SU improved HbA1c levels (median change -1.55% [range -3.8 to 0.1]; P < 0.0001), intelligence scores, hypotonia (in 12 of 15 patients), visual attention deficits (in 10 of 13 patients), gross and fine motor skills (in all patients younger than 4 years old), and gesture conception and realization (in 5 of 8 older patients). Electrophysiological muscle and nerve tests were normal. Cerebral MRI at baseline showed lesions in 12 patients, suggesting that the impairments were central in origin. CONCLUSIONS: SU therapy in neonatal diabetes secondary to mutations in potassium-channel subunits produces measurable improvements in neuropsychomotor impairments, which are greater in younger patients. An early genetic diagnosis should always be made, allowing for a rapid switch to SU.