RESUMO
Diabetic retinopathy is a leading cause of acquired blindness, and it is the most common ischemic disorder of the retina. Available treatments are not very effective. Efforts to inhibit diabetic retinopathy have focused either on highly specific therapeutic approaches for pharmacologic targets or using genetic approaches to change expression of certain enzymes. However, it might be wise to choose innovative treatment modalities that act by multiple potential mechanisms. The resistance to ischemic injury, or ischemic tolerance, can be transiently induced by prior exposure to a non-injurious preconditioning stimulus. A complete functional and histologic protection against retinal ischemic damage can be achieved by previous preconditioning with non-damaging ischemia. In this review, we will discuss evidence that supports that ischemic conditioning could help avert the dreaded consequences that results from retinal diabetic damage.
RESUMO
Diabetic retinopathy is a leading cause of reduced visual acuity and acquired blindness. Available treatments are not completely effective. We analyzed the effect of environmental enrichment on retinal damage induced by experimental diabetes in adult Wistar rats. Diabetes was induced by an intraperitoneal injection of streptozotocin. Three days after vehicle or streptozotocin injection, animals were housed in enriched environment or remained in a standard environment. Retinal function (electroretinogram, and oscillatory potentials), retinal morphology, blood-retinal barrier integrity, synaptophysin, astrocyte and Müller cell glial fibrillary acidic protein, vascular endothelial growth factor, tumor necrosis factor-α, and brain-derived neurotrophic factor levels, as well as lipid peroxidation were assessed in retina from diabetic animals housed in standard or enriched environment. Environmental enrichment preserved scotopic electroretinogram a-wave, b-wave and oscillatory potential amplitude, avoided albumin-Evan's blue leakage, prevented the decrease in retinal synaptophysin and astrocyte glial fibrillary acidic protein levels, the increase in Müller cell glial fibrillary acidic protein, vascular endothelial growth factor and tumor necrosis factor-α levels, as well as oxidative stress induced by diabetes. In addition, enriched environment prevented the decrease in retinal brain-derived neurotrophic factor levels induced by experimental diabetes. When environmental enrichment started 7 weeks after diabetes onset, retinal function was significantly preserved. These results indicate that enriched environment could attenuate the early diabetic damage in the retina from adult rats.
Assuntos
Catarata/prevenção & controle , Diabetes Mellitus Experimental/complicações , Retinopatia Diabética/prevenção & controle , Meio Ambiente , Retina/patologia , Animais , Barreira Hematorretiniana/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Catarata/etiologia , Catarata/metabolismo , Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/etiologia , Retinopatia Diabética/metabolismo , Abrigo para Animais , Masculino , Ratos Wistar , Retina/metabolismo , Sinaptofisina/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Diabetic retinopathy is a leading cause of blindness. Intrinsically photosensitive retinal ganglion cells (ipRGCs), which express the photopigment melanopsin, are involved in non-image-forming visual responses such as photoentrainment of circadian rhythms and pupillary light reflex. Since several reports indicate that retinal ganglion cells are affected by diabetes, we investigated the non-image-forming visual system in an advanced stage of experimental diabetes in rats induced by streptozotocin. After 15 wks of diabetes induction, clear alterations in the visual function were observed and all animals developed mature cataracts. At this time point, concomitantly with a significant decrease in the number of Brn3a(+) retinal ganglion cells, no differences in the number of melanopsin-containing cells, melanopsin levels, and retinal projections to the suprachiasmatic nuclei and the olivary pretectal nucleus were observed. At high light intensity, afferent pupil light reflex appears to be conserved in diabetic animals. After 15 wks of diabetes induction, a significant decrease in light-induced c-Fos expression in the suprachiasmatic nuclei was found. In diabetic animals, the locomotor activity pattern was conserved, although a delay in the time needed for re-entrainment after a phase delay was observed. In diabetic animals, lensectomy reversed the alterations in c-Fos expression and in the locomotor activity rhythm. These results suggest that the neuronal substrate of the non-image-forming visual system remained largely unaffected at advanced stages of diabetes, and that lensectomy, a relatively easy and safe surgery, could partially restore circadian alterations induced by diabetes.
Assuntos
Diabetes Mellitus Experimental/complicações , Retinopatia Diabética/patologia , Fenômenos Fisiológicos Oculares , Animais , Toxina da Cólera , Ritmo Circadiano , Eletrorretinografia , Potenciais Evocados Visuais/fisiologia , Regulação da Expressão Gênica/fisiologia , Genes fos , Masculino , Ratos , Ratos Wistar , Células Ganglionares da Retina/fisiologia , Opsinas de Bastonetes/genética , Opsinas de Bastonetes/metabolismoRESUMO
The aim of this study was to elucidate whether post-ischemic enriched environment (EE) housing protects the retina from ischemic damage in adult rats, and the involvement of glutamate in retinal protection induced by EE housing. For this purpose, ischemia was induced by increasing intraocular pressure to 120 mm Hg for 40 min. After ischemia, animals were housed in a standard environment (SE) or EE and subjected to electroretinography and histological analysis. EE housing afforded significant functional protection in eyes exposed to ischemia/reperfusion injury. A marked reduction in retinal thickness and ganglion cell number, and an increase in Müller cell glial fibrillary acidic protein (GFAP) levels were observed in ischemic retinas from SE-housed animals, which were reversed by EE housing. A deficit in anterograde transport from the retina to the superior colliculus was observed in SE- but not in EE-housed animals. In SE-housed animals, ischemia induced a significant decrease in retinal glutamate uptake and glutamine synthetase activity, whereas EE housing reversed the effect of ischemia on these parameters. The intravitreal injection of supraphysiological levels of glutamate partially reproduced retinal alterations induced by ischemia/reperfusion, which were abrogated by EE housing. These results indicate that EE housing significantly protected retinal function and histology from ischemia/reperfusion injury in adult rats, likely through a glutamate-dependent mechanism.
Assuntos
Meio Ambiente , Isquemia/patologia , Traumatismo por Reperfusão/prevenção & controle , Retina/fisiologia , Doenças Retinianas/prevenção & controle , Animais , Modelos Animais de Doenças , Eletrorretinografia/métodos , Masculino , Ratos , Ratos Wistar , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Retina/patologia , Doenças Retinianas/patologia , Doenças Retinianas/fisiopatologiaRESUMO
Uveitis is a frequent ophthalmic disorder which constitutes one of the main causes of blindness in domestic cats. The aim of this report was to analyze the effect of melatonin on experimentally induced uveitis in cats. Bacterial lipopolysaccharide (LPS) was injected intravitreally into one eye from intact cats, while the contralateral eye was injected with vehicle. Melatonin was orally administered every 24 hr to a group of ten cats, from 24 hr before until 45 days after intravitreal injections. Eyes were evaluated by means of clinical evaluation, intraocular pressure (IOP), blood-ocular barrier integrity (via measurement of protein concentration and cell content in samples of aqueous humor [AH]), electroretinogram (ERG), and histological examination of the retinas. In LPS-treated eyes, several clinical signs were observed until day 45 postinjection. The treatment with melatonin significantly decreased clinical signs and prevented the reduction in IOP induced by LPS. In LPS-injected eyes, melatonin significantly preserved the blood-ocular barrier integrity, as shown by a decrease in the number of infiltrating cells and protein concentration in the AH. Mean amplitudes of scotopic ERG a- and b-waves were significantly reduced in eyes injected with LPS, whereas melatonin significantly prevented the effect of LPS. At 45 days after injection, LPS induced alterations in photoreceptors and at the middle portion of the retina, whereas melatonin preserved the retinal structure. These results indicate that melatonin prevented clinical, biochemical, functional, and histological alterations induced by LPS injection. Thus, melatonin might constitute a useful tool for the treatment of feline uveitis.
Assuntos
Melatonina/farmacologia , Uveíte/tratamento farmacológico , Análise de Variância , Animais , Gatos , Eletrorretinografia/efeitos dos fármacos , Histocitoquímica , Pressão Intraocular/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Retina/química , Retina/efeitos dos fármacos , Retina/patologia , Uveíte/induzido quimicamente , Uveíte/patologia , Uveíte/fisiopatologiaRESUMO
Diabetic retinopathy is a leading cause of acquired blindness. Visual function disorders have been observed in diabetic patients with very early retinopathy or even before the onset of retinopathy. The aim of the present work was to analyze the visual pathway in an early stage of experimental diabetes. Diabetes was induced in Wistar rats by an i.p. injection of streptozotocin. A deficit in anterograde transport from the retina to the superior colliculus was observed 6 weeks after streptozotocin injection. At this time point, morphologic studies did not reveal retinal ganglion cell loss or substantial alterations in the superior colliculus. The optic nerve was morphometrically evaluated at intraorbital (unmyelinated and myelinated) and intracranial sections. In animals that had been diabetic for 6 weeks, a large increase in astrocyte reactivity occurred in the distal (but not the intraorbital) portion, which coincided with significant axon loss. Moreover, profound myelin alterations and altered morphologic features of oligodendrocyte lineage were observed at the distal (but not the proximal) optic nerve portion. The present results suggest that axoglial alterations at the distal portion of the optic nerve could be the first structural change in the diabetic visual pathway.
Assuntos
Axônios/fisiologia , Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Retinopatia Diabética/fisiopatologia , Vias Visuais/fisiologia , Animais , Axônios/ultraestrutura , Contagem de Células , Toxina da Cólera , Corantes , Diabetes Mellitus Experimental/patologia , Neuropatias Diabéticas/patologia , Retinopatia Diabética/patologia , Masculino , Microscopia Eletrônica , Ratos , Ratos Wistar , Células Ganglionares da Retina/fisiologia , Células Ganglionares da Retina/ultraestruturaRESUMO
Diabetic retinopathy is a leading cause of blindness. Visual function disorders have been demonstrated in diabetics even before the onset of retinopathy. At early stages of experimental diabetes, axoglial alterations occur at the distal portion of the optic nerve. Although ischemic conditioning can protect neurons and synaptic terminals against ischemic damage, there is no information on its ability to protect axons. We analyzed the effect of ischemic conditioning on the early axoglial alterations in the distal portion of the optic nerve induced by experimental diabetes. Diabetes was induced in Wistar rats by an intraperitoneal injection of streptozotocin. Retinal ischemia was induced by increasing intraocular pressure to 120 mm Hg for 5 min; this maneuver started 3 days after streptozotocin injection and was weekly repeated in one eye, while the contralateral eye was submitted to a sham procedure. The application of ischemia pulses prevented a deficit in the anterograde transport from the retina to the superior colliculus, as well as an increase in astrocyte reactivity, ultraestructural myelin alterations, and altered morphology of oligodendrocyte lineage in the optic nerve distal portion at early stages of experimental diabetes. Ischemia tolerance prevented a significant decrease of retinal glutamine synthetase activity induced by diabetes. These results suggest that early vision loss in diabetes could be abated by ischemic conditioning which preserved axonal function and structure.
Assuntos
Retinopatia Diabética/patologia , Precondicionamento Isquêmico , Nervo Óptico/irrigação sanguínea , Nervo Óptico/patologia , Células Ganglionares da Retina/patologia , Vias Visuais/irrigação sanguínea , Vias Visuais/patologia , Animais , Astrócitos/metabolismo , Axônios/ultraestrutura , Transporte Biológico , Glicemia , Peso Corporal , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/prevenção & controle , Ativação Enzimática , Glutamato-Amônia Ligase , Masculino , Oligodendroglia/metabolismo , Ratos , Retina/metabolismo , Colículos Superiores/metabolismo , Fatores de Tempo , Fator de Transcrição Brn-3A/metabolismoRESUMO
Glaucoma is a leading cause of acquired blindness which may involve an ischemic-like insult to retinal ganglion cells and optic nerve head. We investigated the effect of a weekly application of brief ischemia pulses (ischemic conditioning) on the rat retinal damage induced by experimental glaucoma. Glaucoma was induced by weekly injections of chondroitin sulfate (CS) in the rat eye anterior chamber. Retinal ischemia was induced by increasing intraocular pressure to 120 mmHg for 5 min; this maneuver started after 6 weekly injections of vehicle or CS and was weekly repeated in one eye, while the contralateral eye was submitted to a sham procedure. Glaucoma was evaluated in terms of: i) intraocular pressure (IOP), ii) retinal function (electroretinogram (ERG)), iii) visual pathway function (visual evoked potentials, (VEPs)) iv) histology of the retina and optic nerve head. Retinal thiobarbituric acid substances levels were assessed as an index of lipid peroxidation. Ischemic conditioning significantly preserved ERG, VEPs, as well as retinal and optic nerve head structure from glaucomatous damage, without changes in IOP. Moreover, ischemia pulses abrogated the increase in lipid peroxidation induced by experimental glaucoma. These results indicate that induction of ischemic tolerance could constitute a fertile avenue for the development of new therapeutic strategies in glaucoma treatment.
Assuntos
Glaucoma/patologia , Glaucoma/prevenção & controle , Isquemia/complicações , Precondicionamento Isquêmico , Células Ganglionares da Retina/patologia , Animais , Glaucoma/induzido quimicamente , Glaucoma/etiologia , Isquemia/prevenção & controle , Peroxidação de Lipídeos , Ratos , Retina/patologiaRESUMO
Diabetic retinopathy is a leading cause of acquired blindness. Available treatments are not very effective. We investigated the effect of a weekly application of retinal ischemia pulses (ischemic conditioning) on retinal damage induced by experimental diabetes. Diabetes was induced by an intraperitoneal injection of streptozotocin. Retinal ischemia was induced by increasing intraocular pressure to 120 mmHg for 5 minutes; this maneuver started 3 days after streptozotocin injection and was weekly repeated in one eye, whereas the contralateral eye was submitted to a sham procedure. Diabetic retinopathy was evaluated in terms of i) retinal function (electroretinogram and oscillatory potentials), ii) integrity of blood-retinal barrier (by albumin-Evans blue complex leakage and astrocyte glial fibrillary acidic protein IHC), iii) optical and electron microscopy histopathologic studies, and iv) vascular endothelial growth factor levels (using Western blot analysis and IHC). Brief ischemia pulses significantly preserved electroretinogram a- and b-wave and oscillatory potentials, avoided albumin-Evans blue leakage, prevented the decrease in astrocyte glial fibrillary acidic protein levels, reduced the appearance of retinal edemas, and prevented the increase in vascular endothelial growth factor levels induced by experimental diabetes. When the application of ischemia pulses started 6 weeks after diabetes onset, retinal function was significantly preserved. These results indicate that induction of ischemic tolerance could constitute a fertile avenue for the development of new therapeutic strategies for diabetic retinopathy treatment.
Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/patologia , Retinopatia Diabética/prevenção & controle , Precondicionamento Isquêmico/métodos , Animais , Barreira Hematorretiniana/patologia , Western Blotting , Eletrorretinografia , Imuno-Histoquímica , Masculino , Microscopia Eletrônica de Transmissão , Ratos , Ratos WistarRESUMO
Glaucoma is a leading cause of blindness worldwide, characterized by retinal ganglion cell degeneration and damage to the optic nerve. We investigated the non-image forming visual system in an experimental model of glaucoma in rats induced by weekly injections of chondroitin sulphate (CS) in the eye anterior chamber. Animals were unilaterally or bilaterally injected with CS or vehicle for 6 or 10 weeks. In the retinas from eyes injected with CS, a similar decrease in melanopsin and Thy-1 levels was observed. CS injections induced a similar decrease in the number of melanopsin-containing cells and superior collicular retinal ganglion cells. Experimental glaucoma induced a significant decrease in the afferent pupil light reflex. White light significantly decreased nocturnal pineal melatonin content in control and glaucomatous animals, whereas blue light decreased this parameter in vehicle- but not in CS-injected animals. A significant decrease in light-induced c-Fos expression in the suprachiasmatic nuclei was observed in glaucomatous animals. General rhythmicity and gross entrainment appear to be conserved, but glaucomatous animals exhibited a delayed phase angle with respect to lights off and a significant increase in the percentage of diurnal activity. These results indicate the glaucoma induced significant alterations in the non-image forming visual system.