RESUMEN
Glaucoma, the leading cause of irreversible blindness worldwide, is a neurodegenerative disease characterized by chronic axonal damages and progressive loss of retinal ganglion cells, with increased intraocular pressure (IOP) as the primary risk factor. While current treatments focus solely on reducing IOP, understanding glaucoma through experimental models is essential for developing new therapeutic strategies and biomarkers for early diagnosis. Our research group developed an ocular hypertension rat model based on limbal plexus cautery, which provides significant glaucomatous neurodegeneration up to four weeks after injury. We evaluated long-term morphological, functional, and vascular alterations in this model. Our results showed that transient ocular hypertension, lasting approximately one week, can lead to progressive increase in optic nerve cupping and retinal ganglion cells loss. Remarkably, the pressure insult caused several vascular changes, such as arteriolar and venular thinning, and permanent choroidal vascular swelling. This study provides evidence of the longitudinal effects of a pressure insult on retinal structure and function using clinical modalities and techniques. The multifactorial changes reported in this model resemble the complex retinal ganglion cell degeneration found in glaucoma patients, and therefore may also provide a unique tool for the development of novel interventions to either halt or slow down disease progression.
Asunto(s)
Modelos Animales de Enfermedad , Glaucoma , Presión Intraocular , Células Ganglionares de la Retina , Animales , Ratas , Glaucoma/fisiopatología , Glaucoma/patología , Células Ganglionares de la Retina/patología , Presión Intraocular/fisiología , Vasos Retinianos/patología , Vasos Retinianos/fisiopatología , Hipertensión Ocular/fisiopatología , Hipertensión Ocular/patología , Ratas Sprague-DawleyRESUMEN
Recombinant adeno-associated viral vectors (rAAV) are the safest and most effective gene delivery platform to drive the treatment of many inherited eye disorders in well-characterized animal models. The use in rAAV of ubiquitous promoters derived from viral sequences such as CMV/CBA (chicken ß-actin promoter with cytomegalovirus enhancer) can lead to unwanted side effects such as pro-inflammatory immune responses and retinal cytotoxicity, thus reducing therapy efficacy. Thus, an advance in gene therapy is the availability of small promoters, that potentiate and direct gene expression to the cell type of interest, with higher safety and efficacy. In this study, we used six human mini-promoters packaged in rAAV2 quadruple mutant (Y-F) to test for transduction of the rat retina after intravitreal injection. After four weeks, immunohistochemical analysis detected GFP-labeled cells in the ganglion cell layer (GCL) for all constructs tested. Among them, Ple25sh1, Ple25sh2 and Ple53 promoted a widespread reporter-transgene expression in the GCL, with an increased number of GFP-expressing retinal ganglion cells when compared with the CMV/CBA vector. Moreover, Ple53 provided the strongest levels of GFP fluorescence in both cell soma and axons of retinal ganglion cells (RGCs) without any detectable adverse effects in retina function. Remarkably, a nearly 50-fold reduction in the number of intravitreally injected vector particles containing Ple53 promoter, still attained levels of transgene expression similar to CMV/CBA. Thus, the tested MiniPs show great potential for protocols of retinal gene therapy in therapeutic applications for retinal degenerations, especially those involving RGC-related disorders such as glaucoma.
Asunto(s)
Infecciones por Citomegalovirus , Células Ganglionares de la Retina , Ratas , Humanos , Animales , Células Ganglionares de la Retina/metabolismo , Vectores Genéticos , Retina/metabolismo , Transgenes , Inyecciones Intravítreas , Infecciones por Citomegalovirus/genética , Infecciones por Citomegalovirus/metabolismo , Dependovirus/genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Transducción GenéticaRESUMEN
SUMMARY: The distribution of retinal ganglion cells (RGCs) was observed in the retinal wholemount of native chicken (Gallus gallus domestricus) of Bangladesh by using light microscopy. We considered five different anatomic regions (central, nasal, temporal, dorsal, and ventral) of Nissl stained wholemount, and the RGCs were counted, plotted, and measured accordingly. The average area of the retina was 431.75 mm2 while the total number of ganglion cells was 2124431 on average. Only the central area of the retina was the peak density (10400 cells/mm2) area, signifying the acute visual area, whilst the maximum spatial resolving power was 11 cycles/degree. The overall concentration of RGCs gradually declined towards the periphery but the size of cells generally decreased towards centrally. The size of ganglion cell was not uniform (12 to 180 µm2), specifically the central retina, just above the optic disc was packed with tiny-sized cells. The number, topographic distribution, and size of RGCs in native chicken signified their domesticated or terrestrial characters, uneven visual acuteness, and possibly only the central retina was the area for fine vision as the function of RGCs.
RESUMEN: En este studio se observó la distribución de las células ganglionares en la retina (CGR) de pollo nativo (Gallus gallus domesticus) de Bangladesh mediante el uso de microscopía óptica. Consideramos cinco regiones anatómicas diferentes (central, nasal, temporal, dorsal y ventral). Las muestras de CGR se tiñeron con Nissl, posteriormente, se midieron y contó el número de células totales. El área promedio de la retina fue de 431,75 mm2, mientras que el promedio del número total de células ganglionares fue de 2124431. El área central de la retina fue el área de densidad máxima (10400 células / mm2), señalando el área visual aguda, mientras que el poder de resolución espacial máximo fue de 11 ciclos / grado. La concentración general de CGR disminuyó gradualmente hacia la periferia, sin embargo, el tamaño de las células disminuyó hacia el centro. El tamaño de las CGR no fue uniforme (12 a 180 mm2), específicamente en la retina central, por encima del disco óptico, aumentaron significativamente las células pequeñas. El número, la distribución topográfica y el tamaño de las CGR en pollos nativos determinaron las características domésticas o terrestres, agudeza visual desigual y, posiblemente, la función de las CGR, en la retina central era el área de visión fina.
Asunto(s)
Animales , Células Ganglionares de la Retina/citología , Pollos/anatomía & histología , Bangladesh , MicroscopíaRESUMEN
Glaucoma is a multifactorial neurodegenerative disease, characterized by degeneration of the retinal ganglion cells (RGCs). There has been little progress in developing efficient strategies for neuroprotection in glaucoma. We profiled the retina transcriptome of Lister Hooded rats at 2 weeks after optic nerve crush (ONC) and analyzed the data from the genomic fabric paradigm (GFP) to bring additional insights into the molecular mechanisms of the retinal remodeling after induction of RGC degeneration. GFP considers three independent characteristics for the expression of each gene: level, variability, and correlation with each other gene. Thus, the 17,657 quantified genes in our study generated a total of 155,911,310 values to analyze. This represents 8830x more data per condition than a traditional transcriptomic analysis. ONC led to a 57% reduction in RGC numbers as detected by retrograde labeling with 1,1'-dioctadecyl-3,3,3,3'-tetramethylindocarbocyanine perchlorate (DiI). We observed a higher relative expression variability after ONC. Gene expression stability was used as a measure of transcription control and disclosed a robust reduction in the number of very stably expressed genes. Predicted protein-protein interaction (PPI) analysis with STRING revealed axon and neuron projection as mostly decreased processes, consistent with RGC degeneration. Conversely, immune response PPIs were found among upregulated genes. Enrichment analysis showed that complement cascade and Notch signaling pathway, as well as oxidative stress and kit receptor pathway were affected after ONC. To expand our studies of altered molecular pathways, we examined the pairwise coordination of gene expressions within each pathway and within the entire transcriptome using Pearson correlations. ONC increased the number of synergistically coordinated pairs of genes and the number of similar profiles mainly in complement cascade and Notch signaling pathway. This deep bioinformatic study provided novel insights beyond the regulation of individual gene expression and disclosed changes in the control of expression of complement cascade and Notch signaling functional pathways that may be relevant for both RGC degeneration and remodeling of the retinal tissue after ONC.
Asunto(s)
Glaucoma , Traumatismos del Nervio Óptico , Nervio Óptico , Células Ganglionares de la Retina , Transcriptoma , Animales , Femenino , Glaucoma/genética , Glaucoma/metabolismo , Glaucoma/patología , Nervio Óptico/metabolismo , Nervio Óptico/patología , Traumatismos del Nervio Óptico/genética , Traumatismos del Nervio Óptico/metabolismo , Traumatismos del Nervio Óptico/patología , Ratas , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patologíaRESUMEN
Glaucoma leads to irreversible vision loss and current therapeutic strategies are often insufficient to prevent the progression of the disease and consequent blindness. Elevated intraocular pressure is an important risk factor, but not required for the progression of glaucomatous neurodegeneration. The demise of retinal ganglion cells represents the final common pathway of glaucomatous vision loss. Still, lifelong control of intraocular pressure is the only current treatment to prevent severe vision loss, although it frequently fails despite best practices. This scenario calls for the development of neuroprotective and pro-regenerative therapies targeting the retinal ganglion cells as well as the optic nerve. Several experimental studies have shown the potential of gene modulation as a tool for neuroprotection and regeneration. In this context, gene therapy represents an attractive approach as a persistent treatment for glaucoma. Viral vectors engineered to promote overexpression of a broad range of cellular factors have been shown to protect retinal ganglion cells and/or promote axonal regeneration in experimental models. Here, we review the mechanisms involved in glaucomatous neurodegeneration and regeneration in the central nervous system. Then, we point out the current limitations of gene therapy platforms and review a myriad of studies that use viral vectors to manipulate genes in retinal ganglion cells, as a strategy to promote neuroprotection and regeneration. Finally, we address the potential of combining neuroprotective and regenerative gene therapies as an approach to glaucomatous neurodegeneration.
Asunto(s)
Glaucoma , Terapia Genética , Glaucoma/genética , Glaucoma/terapia , Humanos , Presión Intraocular , Neuroprotección , Células Ganglionares de la RetinaRESUMEN
ABSTRACT Objective: The effect of antipsychotic (AP) drugs on optical coherence tomography (OCT) findings in schizophrenia has not yet been fully elucidated. In this study, we aimed to investigate the effects of APs (the first generation antipsychotic group [FGAG], the second generation antipsychotic group [SGAG], the clozapine group [CG]) on OCT findings in schizophrenia. Methods: The thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), and choroidal thickness were measured using a spectral OCT device. Results: No significant difference was found between FGAG, SGAG, CG (p > 0.05) while there was a significant difference between the control group and the patients group in terms of RNFL, GCL, and IPL (p < 0.05). A significant difference between SGAG and CG, FGAG (p < 0.05); between control group and FGAG (p < 0.05) were found in terms of choroidal thickness. Conclusion: These findings suggested the deterioration of the metabolic parameters due to the SGA use. Thinner choroidal layer thickness in the CG compared to the SGAG and control group was thought to be related to the patients using clozapine had a resistance to the treatment.
RESUMEN
We are reporting for the first time the synthesis and application of an innovative nanometric system for the controlled topic release of melatonin in the retina. The ethylcellulose nanocapsules were characterized by diverse physicochemical techniques (scanning electron microscopy, zeta potential, hydrodynamic diameters) and an in vitro release study was done. A complete ex vivo and in vivo trans-corneal permeation and an irritation study were carried out with the new formulations in albino rabbits, to which a retinal degenerative model was induced. The results obtained demonstrate that the in vitro release of melatonin (1 mg/mL and 2 mg/mL) transported by nanocapsules is slower when compared to a solution of melatonin. Greater penetration of melatonin through the cornea was demonstrated by ex vivo and in vivo tests. This can be attributable to an enhanced neuroprotective effect of melatonin on retinal ganglion cells when it is included in ethylcellulose nanocapsules compared to a solution of melatonin. These outstanding findings add promising new perspectives to current knowledge about administrations using nano-technological tools in the treatment of neurodegenerative diseases at the ocular level.
Asunto(s)
Celulosa/análogos & derivados , Melatonina/administración & dosificación , Degeneración Retiniana/tratamiento farmacológico , Células Ganglionares de la Retina/patología , Animales , Antioxidantes/administración & dosificación , Celulosa/farmacología , Modelos Animales de Enfermedad , Composición de Medicamentos , Microscopía Electrónica de Rastreo , Nanopartículas/ultraestructura , Conejos , Degeneración Retiniana/diagnóstico , Células Ganglionares de la Retina/efectos de los fármacosRESUMEN
ABSTRACT Purpose: To evaluate the inner retinal and choroidal thicknesses in patients with early retinitis pigmentosa. Methods: We analyzed spectral-domain optical coherence tomography images of 35 retinitis pigmentosa patients and 40 healthy individuals. We measured macular and ganglion cell complex thicknesses. We took choroidal thickness measurements in the subfoveal region and 500, 1,000, and 1,500 mm from the foveal center. Results: Patients with retinitis pigmentosa had significantly thinner macular thicknesses and choroidal thicknesses in all measurements, and their individual ganglion cell complex thickness measurements were lower than those in healthy individuals. The mean ganglion cell complex thickness was significantly lower in patients with retinitis pigmentosa than that in controls. The mean macular thickness was significantly correlated with the mean choroidal and mean ganglion cell complex thicknesses. (We found no correlation between the mean choroidal thickness and the mean ganglion cell complex thickness). Conclusions: The choroid was mildly affected in our patients with early retinitis pigmentosa. The tendency toward significance in the inner retina was possibly caused by a good visual acuity.
RESUMO Objetivo: Avaliar as espessuras internas da retina e da coroide em pacientes com retinite pigmentosa precoce. Métodos: Foram analisadas imagens de tomografia de coerência óptica de domínio espectral de 35 pacientes com retinite pigmentosa e 40 indivíduos saudáveis. Medimos a espessura do complexo de células maculares e ganglionares. Realizamos medições da espessura da coroide na região subfoveal e a 500 mm, 1000 mm e 1500 mm do centro da fóvea. Resultados: Pacientes com retinite pigmentosa apresentaram espessuras maculares e da coroide significativamente mais finas em todas as medições e suas medidas individuais da espessura do complexo de células ganglionares foram inferiores às de indivíduos saudáveis. A espessura média do complexo de células ganglionares foi significativamente menor nos pacientes com retinite pigmentosa do que nos controles. A espessura macular média foi significativamente correlacionada com as espessuras médias do complexo das células de coroide e das células ganglionares médias. Não encontramos correlação entre a espessura media da coroide e a espessura media do complexo de células ganglionares. Conclusões: A coroide foi levemente afetada em nossos pacientes com retinite pigmentosa precoce. A tendência à significância na retina interna foi possivelmente causada por uma boa acuidade visual.
Asunto(s)
Humanos , Retinitis Pigmentosa , Coroides/diagnóstico por imagen , Tomografía de Coherencia Óptica , Retina/diagnóstico por imagen , Agudeza Visual , Retinitis Pigmentosa/diagnóstico por imagenRESUMEN
PURPOSE: The current study was undertaken to investigate whether Brazilian green propolis (BGP) can increase the viability of retinal ganglion cells (RGCs) in ischemic mouse retina, and examined the possible mechanisms underlying this neuroprotection. MATERIALS AND METHODS: C57BL/6J mice were subjected to constant elevation of intraocular pressure for 60 min to establish retinal ischemia-reperfusion injury. Mice then received saline or BGP (200 mg/kg) intraperitoneally once daily until sacrifice. The expression of hypoxia-inducing factor (HIF)-1α and glial fibrillary acidic protein (GFAP) and the level of histone acetylation were assessed at 1, 3, and 7 days after injury. The expression of Bax, Bcl-2, p53, NF-κB, Nrf2, and HO-1 were also analyzed at 3 days after injury. The neuroprotective effect of BGP treatment on RGC survival was evaluated using Brn3a immunohistochemical staining. RESULTS: The expression of HIF-1α and GFAP was increased and the level of histone acetylation decreased in saline-treated ischemic retinas within 7 days. BGP treatment effectively attenuated the elevated expression of HIF-1α, GFAP, Bax, NF-κB and p53. The expression of Bcl-2, Nrf2, HO-1 and the level of histone acetylation increased by BGP treatment, resulting in a significant difference between BGP-treated and saline-treated retinas. Immunohistochemical staining for Brn3a also revealed that BGP treatment protected against RGC loss in ischemic retina. CONCLUSIONS: Our results suggest that BGP has a neuroprotective effect on RGCs through the upregulation of histone acetylation, downregulation of apoptotic stimuli, and suppression of NF-κB mediated inflammatory pathway in ischemic retina. These findings suggest that BGP is a potential neuroprotective agent against RGC loss under oxidative stress.
Asunto(s)
Fármacos Neuroprotectores/uso terapéutico , Própolis/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Enfermedades de la Retina/tratamiento farmacológico , Células Ganglionares de la Retina/efectos de los fármacos , Acetilación , Animales , Brasil , Supervivencia Celular , Proteína Ácida Fibrilar de la Glía/metabolismo , Histonas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inyecciones Intraperitoneales , Ratones , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/química , Estrés Oxidativo , Própolis/química , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/patología , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Factor de Transcripción Brn-3A/metabolismo , Regulación hacia ArribaRESUMEN
Purpose: The photopic negative response (PhNR) is an electrophysiological method that provides retinal ganglion cell function assessment using full-field stimulation that does not require clear optics or refractive correction. The purpose of this study was to assess ganglion cell function by PhNR in affected and asymptomatic carriers from Brazilian families with LHON. Methods: Individuals either under suspicion or previously diagnosed with LHON and their family members were invited to participate in this cross-sectional study. Screening for the most frequent LHON mtDNA mutations was performed. Visual acuity, color discrimination, visual fields, pattern-reversal visual evoked potentials (PRVEP), full-field electroretinography and PhNR were tested. A control group of healthy subjects was included. Full-field ERG PhNR were recorded using red (640 nm) flashes at 1 cd.s/m2, on blue (470 nm) rod saturating background. PhNR amplitude (µV) was measured using baseline-to-trough (BT). Optical coherence tomography scans of both the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) were measured. PhNR amplitudes among affected, carriers and controls were compared by Kruskal-Wallis test followed by post-hoc Dunn test. The associations between PhNR amplitude and OCT parameters were analyzed by Spearman rank correlation. Results: Participants were 24 LHON affected patients (23 males, mean age=30.5 ± 11.4 yrs) from 19 families with the following genotype: m.11778G>A [N = 15 (62%), 14 males]; m.14484T>C [N = 5 (21%), all males] and m.3460G>A [N = 4 (17%), all males] and 14 carriers [13 females, mean age: 43.2 ± 13.3 yrs; m.11778G>A (N = 11); m.3460G>A (N = 2) and m.14484T>C (N = 1)]. Controls were eight females and seven males (mean age: 32.6 ± 11.5 yrs). PhNR amplitudes were significantly reduced (p = 0.0001) in LHON affected (-5.96 ± 3.37 µV) compared to carriers (-16.53 ± 3.40 µV) and controls (-23.91 ± 4.83; p < 0.0001) and in carriers compared to controls (p = 0.01). A significant negative correlation was found between PhNR amplitude and total macular ganglion cell thickness (r = -0.62, p < 0.05). Severe abnormalities in color discrimination, visual fields and PRVEPs were found in affected and subclinical abnormalities in carriers. Conclusions: In this cohort of Brazilian families with LHON the photopic negative response was severely reduced in affected patients and mildly reduced in asymptomatic carriers suggesting possible subclinical abnormalities in the latter. These findings were similar among pathogenic mutations.
RESUMEN
Millones de pacientes con glaucoma pierden la visión, por lo que es una necesidad para desarrollar terapias neuroprotectoras que pueden utilizarse en conjunción con medicamentos hipotensores, para prevenir la muerte de las células ganglionares de la retina (CGR). Los recientes avances en la comprensión de la fisiopatología de glaucoma es un factor clave en la patogénesis de la neuropatía glaucomatosa. Con base en los hallazgos en enfermedades similares, la hipótesis de que la mejora del flujo sanguíneo de la retina nervio óptico puede dar lugar a una protección significativa en CGR y prevenir la pérdida de visión en el glaucoma. Sildenafil, un fármaco vasodilatador que inhibe la PDE5, lo que aumenta los niveles de cGMP y la prolongación de sus efectos, y se ha demostrado que mejora la supervivencia de diversas lesiones degenerativas. Esta breve revisión resume los avances más importantes que tenían el conocimiento de esta enfermedad y su posible tratamiento.
Milhões de pacientes com glaucoma irão perder a visão, tornando-se uma necessidade desenvolver terapias neuroprotetoras que possam ser usadas, em conjunção com medicamentos hipotensores, para impedir a morte de células ganglionares da retina (CGR). Recentes avanços na compreensão da fisiopatologia do glaucoma são um fator chave na patogênese da neuropatia glaucomatosa. Com base nos achados em doenças semelhantes, a hipótese de que melhorando o fluxo sanguíneo do nervo óptico da retina possa resultar em uma proteção significativa nas CGR e prevenir a perda da visão no glaucoma. O sildenafil, uma droga vasodilatadora que inibe PDE5, aumentando assim os níveis de cGMP e prolongando seus efeitos, sendo que foi demonstrado melhorar a sobrevivência de várias lesões degenerativas. Esta breve revisão resume alguns dos avanços mais importantes que tiveram no entendimento sobre esta doença e um possível tratamento.
As millions of glaucoma patients lose sight, it has become accepted that there is a need to develop neuroprotective therapies that can be used, in conjunction with hypotensive drugs, to prevent retinal ganglion cell (RGC) death. Recent advances in the understanding of the pathophysiology of glaucoma is a key factor in the pathogenesis of glaucomatous neuropathy. Based on findings in similar diseases, hypothesize that improving retinal and optic nerve blood flow can result in significant RGC protection and prevent vision loss in glaucoma. Sildenafil, a vasodilative drug that inhibits PDE5, thereby increasing cGMP levels and prolonging NO effects, has been shown to improve survival in several injury. This short review briefly summarizes some of the most important advances that have taken in the understand about this disease and a possible treatment.
Asunto(s)
Apoptosis/fisiología , Células Ganglionares de la Retina , Glaucoma/fisiopatología , Glaucoma/patología , Glaucoma/terapia , Fármacos NeuroprotectoresRESUMEN
Millones de pacientes con glaucoma pierden la visión, por lo que es una necesidad para desarrollar terapias neuroprotectoras que pueden utilizarse en conjunción con medicamentos hipotensores, para prevenir la muerte de las células ganglionares de la retina (CGR). Los recientes avances en la comprensión de la fisiopatología de glaucoma es un factor clave en la patogénesis de la neuropatía glaucomatosa. Con base en los hallazgos en enfermedades similares, la hipótesis de que la mejora del flujo sanguíneo de la retina nervio óptico puede dar lugar a una protección significativa en CGR y prevenir la pérdida de visión en el glaucoma. Sildenafil, un fármaco vasodilatador que inhibe la PDE5, lo que aumenta los niveles de cGMP y la prolongación de sus efectos, y se ha demostrado que mejora la supervivencia de diversas lesiones degenerativas. Esta breve revisión resume los avances más importantes que tenían el conocimiento de esta enfermedad y su posible tratamiento.(AU)
Milhões de pacientes com glaucoma irão perder a visão, tornando-se uma necessidade desenvolver terapias neuroprotetoras que possam ser usadas, em conjunção com medicamentos hipotensores, para impedir a morte de células ganglionares da retina (CGR). Recentes avanços na compreensão da fisiopatologia do glaucoma são um fator chave na patogênese da neuropatia glaucomatosa. Com base nos achados em doenças semelhantes, a hipótese de que melhorando o fluxo sanguíneo do nervo óptico da retina possa resultar em uma proteção significativa nas CGR e prevenir a perda da visão no glaucoma. O sildenafil, uma droga vasodilatadora que inibe PDE5, aumentando assim os níveis de cGMP e prolongando seus efeitos, sendo que foi demonstrado melhorar a sobrevivência de várias lesões degenerativas. Esta breve revisão resume alguns dos avanços mais importantes que tiveram no entendimento sobre esta doença e um possível tratamento.(AU)
As millions of glaucoma patients lose sight, it has become accepted that there is a need to develop neuroprotective therapies that can be used, in conjunction with hypotensive drugs, to prevent retinal ganglion cell (RGC) death. Recent advances in the understanding of the pathophysiology of glaucoma is a key factor in the pathogenesis of glaucomatous neuropathy. Based on findings in similar diseases, hypothesize that improving retinal and optic nerve blood flow can result in significant RGC protection and prevent vision loss in glaucoma. Sildenafil, a vasodilative drug that inhibits PDE5, thereby increasing cGMP levels and prolonging NO effects, has been shown to improve survival in several injury. This short review briefly summarizes some of the most important advances that have taken in the understand about this disease and a possible treatment.(AU)
Asunto(s)
Glaucoma/patología , Glaucoma/fisiopatología , Glaucoma/terapia , Apoptosis/fisiología , Células Ganglionares de la Retina , Fármacos NeuroprotectoresRESUMEN
BACKGROUND: Retinal ganglion cell (RGC) differentiation in vivo is a highly stereotyped process, likely resulting from the interaction of cell type-specific transcription factors and tissue-derived signaling factors. The primary cilium, as a signaling hub in the cell, may have a role during this process but its presence and localization during RGC generation, and its contribution to the process of cell differentiation, have not been previously assessed in vivo. METHODS: In this work we analyzed the distribution of primary cilia in vivo using laser scanning confocal microscopy, as well as their main ultrastructural features by transmission electron microscopy, in the early stages of retinal histogenesis in the zebrafish, around the time of RGC generation and initial differentiation. In addition, we knocked-down ift88 and elipsa, two genes with an essential role in cilia generation and maintenance, a treatment that caused a general reduction in organelle size. The effect on retinal development and RGC differentiation was assessed by confocal microscopy of transgenic or immunolabeled embryos. RESULTS: Our results show that retinal neuroepithelial cells have an apically-localized primary cilium usually protruding from the apical membrane. We also found a small proportion of sub-apical cilia, before and during the neurogenic period. This organelle was also present in an apical position in neuroblasts during apical process retraction and dendritogenesis, although between these stages cilia appeared highly dynamic regarding both presence and position. Disruption of cilia caused a decrease in the proliferation of retinal progenitors and a reduction of neural retina volume. In addition, retinal histogenesis was globally delayed albeit RGC layer formation was preferentially reduced with respect to the amacrine and photoreceptor cell layers. CONCLUSIONS: These results indicate that primary cilia exhibit a highly dynamic behavior during early retinal differentiation, and that they are required for the proliferation and survival of retinal progenitors, as well as for neuronal generation, particularly of RGCs.
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Diferenciación Celular , Cilios/fisiología , Cilios/ultraestructura , Retina/embriología , Retina/ultraestructura , Células Ganglionares de la Retina/fisiología , Células Ganglionares de la Retina/ultraestructura , Animales , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Técnicas de Silenciamiento del Gen , Neurogénesis , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
PURPOSE: We measured macular inner retinal layer thicknesses using frequency-domain optical coherence tomography (fd-OCT) and correlated these measures with visual field (VF) in eyes with temporal hemianopia from chiasmal compression and band atrophy (BA) of the optic nerve. METHODS: Macular fd-OCT scans and VFs were obtained from 33 eyes of 33 patients with temporal hemianopia and 36 control eyes. The macular retinal nerve fiber layer (mRNFL), combined retinal ganglion cell and inner plexiform layers (RGCL+), and the inner nuclear layer (INL) were segmented. Measurements were averaged for each macula quadrant. Scans were assessed qualitatively for microcysts in the INL. The VF was estimated from the central 16 test points. The two groups were compared. Correlations between VF and OCT measurements were assessed. RESULTS: The mRNFL, RGCL+, and total retinal (TR) macular thickness measurements were significantly smaller in BA eyes than controls. In the nasal quadrants, INL measurements were significantly greater in BA eyes than controls. The mRNFL and RGCL+ measurements had greater discrimination ability than TR measurements in the temporal quadrants. A significant correlation was found between most OCT parameters and their corresponding VF parameters. The strongest association was observed between RNFL and RGCL+ thickness, and VF loss in the corresponding area. The INL microcysts were found in seven eyes with BA, but not in controls. CONCLUSIONS: Band atrophy leads to mRNFL and RGCL+ thinning, and INL thickening, and mRNFL and RGCL+ measurements are correlated strongly with VF loss. Segmented macular thickness measurements may be useful for quantifying neuronal loss in chiasmal compression.
Asunto(s)
Hemianopsia/diagnóstico , Mácula Lútea/patología , Quiasma Óptico/patología , Enfermedades del Nervio Óptico/diagnóstico , Células Ganglionares de la Retina/patología , Tomografía de Coherencia Óptica/métodos , Campos Visuales/fisiología , Adulto , Constricción Patológica , Estudios Transversales , Femenino , Estudios de Seguimiento , Hemianopsia/etiología , Hemianopsia/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Enfermedades del Nervio Óptico/complicaciones , Enfermedades del Nervio Óptico/fisiopatología , Estudios Prospectivos , Pruebas del Campo Visual , Adulto JovenRESUMEN
Motion detection is one of the most important and primitive computations performed by our visual system. Specifically in the retina, ganglion cells producing motion direction-selective responses have been addressed by different disciplines, such as mathematics, neurophysiology and computational modeling, since the beginnings of vision science. Although a number of studies have analyzed theoretical and mathematical considerations for such responses, a clear picture of the underlying cellular mechanisms is only recently emerging. In general, motion direction selectivity is based on a non-linear asymmetric computation inside a receptive field differentiating cell responses between preferred and null direction stimuli. To what extent can biological findings match these considerations? In this review, we outline theoretical and mathematical studies of motion direction selectivity, aiming to map the properties of the models onto the neural circuitry and synaptic connectivity found in the retina. Additionally, we review several compartmental models that have tried to fill this gap. Finally, we discuss the remaining challenges that computational models will have to tackle in order to fully understand the retinal motion direction-selective circuitry.
Asunto(s)
Modelos Teóricos , Percepción de Movimiento/fisiología , Retina/citología , Retina/fisiología , Células Amacrinas/fisiología , Animales , Humanos , Inhibición Neural/fisiología , Células Ganglionares de la Retina/fisiología , Vías Visuales/citología , Vías Visuales/fisiologíaRESUMEN
Agmatine has neuroprotective effects on retinal ganglion cells (RGCs) as well as cortical and spinal neurons. It protects RGCs from oxidative stress even when it is not present at the time of injury. As agmatine has high affinity for various cellular receptors, we assessed protective mechanisms of agmatine using transformed RGCs (RGC-5 cell line). Differentiated RGC-5 cells were pretreated with 100 ìM agmatine and consecutively exposed to 1.0 mM hydrogen peroxide (H2O2). Cell viability was determined by measuring lactate dehydrogenase (LDH), and the effects of selective alpha 2-adrenergic receptor antagonist yohimbine (0-500 nM) and N-methyl-D-aspartic acid (NMDA) receptor agonist NMDA (0-100 µM) were evaluated. Agmatines protective effect was compared to a selective NMDA receptor antagonist MK-801. After a 16-h exposure to H2O2, the LDH assay showed cell loss greater than 50 percent, which was reduced to about 30 percent when agmatine was pretreated before injury. Yohimbine almost completely inhibited agmatines protective effect, but NMDA did not. In addition, MK-801 (0-100 µM) did not significantly attenuate the H2O2-induced cytotoxicity. Our results suggest that neuroprotective effects of agmatine on RGCs under oxidative stress may be mainly attributed to the alpha 2-adrenergic receptor signaling pathway.