RESUMEN
BNN27, a C17-spiroepoxy derivative of DHEA, was shown to have antiapoptotic properties via mechanisms involving the nerve growth factor receptors (tropomyosin-related kinase A [TrkA]/neurotrophin receptor p75 [p75NTR]). In this study, we examined the effects of BNN27 on neural/glial cell function, apoptosis, and inflammation in the experimental rat streptozotocin (STZ) model of diabetic retinopathy (DR). The ability of BNN27 to activate the TrkA receptor and regulate p75NTR expression was investigated. BNN27 (2,10, and 50 mg/kg i.p. for 7 days) administration 4 weeks post-STZ injection (paradigm A) reversed the diabetes-induced glial activation and loss of function of amacrine cells (brain nitric oxide synthetase/tyrosine hydroxylase expression) and ganglion cell axons via a TrkA receptor (TrkAR)-dependent mechanism. BNN27 activated/phosphorylated the TrkAY490 residue in the absence but not the presence of TrkAR inhibitor and abolished the diabetes-induced increase in p75NTR expression. However, it had no effect on retinal cell death (TUNEL+ cells). A similar result was observed when BNN27 (10 mg/kg i.p.) was administered at the onset of diabetes, every other day for 4 weeks (paradigm B). However, BNN27 decreased the activation of caspase-3 in both paradigms. Finally, BNN27 reduced the proinflammatory (TNFα and IL-1ß) and increased the anti-inflammatory (IL-10 and IL-4) cytokine levels. These findings suggest that BNN27 has the pharmacological profile of a therapeutic for DR, since it targets both the neurodegenerative and inflammatory components of the disease.
Asunto(s)
Células Amacrinas/efectos de los fármacos , Antiinflamatorios/uso terapéutico , Deshidroepiandrosterona/uso terapéutico , Retinopatía Diabética/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Receptor trkA/agonistas , Retina/efectos de los fármacos , Células Amacrinas/inmunología , Células Amacrinas/metabolismo , Células Amacrinas/patología , Animales , Antiinflamatorios/administración & dosificación , Axones/efectos de los fármacos , Axones/inmunología , Axones/metabolismo , Axones/patología , Deshidroepiandrosterona/administración & dosificación , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/fisiopatología , Retinopatía Diabética/inmunología , Retinopatía Diabética/metabolismo , Retinopatía Diabética/patología , Relación Dosis-Respuesta a Droga , Proteínas del Ojo/agonistas , Proteínas del Ojo/metabolismo , Femenino , Ganglios Sensoriales/efectos de los fármacos , Ganglios Sensoriales/inmunología , Ganglios Sensoriales/metabolismo , Ganglios Sensoriales/patología , Masculino , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/metabolismo , Neuroglía/efectos de los fármacos , Neuroglía/inmunología , Neuroglía/metabolismo , Neuroglía/patología , Fármacos Neuroprotectores/administración & dosificación , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Ratas Sprague-Dawley , Receptor de Factor de Crecimiento Nervioso/agonistas , Receptor de Factor de Crecimiento Nervioso/metabolismo , Receptor trkA/metabolismo , Retina/inmunología , Retina/patología , Retina/fisiopatología , EstreptozocinaRESUMEN
Major histocompatibility complex (MHC) class I molecules and their receptors play fundamental roles in neuronal death during diseases. T-cell receptors (TCR) function as MHCI receptor on T-cells and both MHCI and a key component of TCR, CD3ζ, are expressed by mouse retinal ganglion cells (RGCs) and displaced amacrine cells. Mutation of these molecules compromises the development of RGCs. We investigated whether CD3ζ regulates the development and degeneration of amacrine cells after RGC death. Surprisingly, mutation of CD3ζ not only impairs the proper development of amacrine cells expressing CD3ζ but also those not expressing CD3ζ. In contrast to effects of MHCI and its receptor, PirB, on other neurons, mutation of CD3ζ has no effect on RGC death and starburst amacrine cells degeneration after optic nerve crush. Thus, unlike MHCI and PirB, CD3ζ regulates the development of RGCs and amacrine cells but not their degeneration after optic nerve crush.
Asunto(s)
Complejo CD3/inmunología , Traumatismos del Nervio Óptico/patología , Nervio Óptico/patología , Células Ganglionares de la Retina/patología , Células Amacrinas/inmunología , Células Amacrinas/patología , Animales , Complejo CD3/genética , Muerte Celular , Dendritas/inmunología , Dendritas/patología , Ratones Endogámicos C57BL , Mutación , Compresión Nerviosa , Nervio Óptico/citología , Nervio Óptico/inmunología , Traumatismos del Nervio Óptico/genética , Traumatismos del Nervio Óptico/inmunología , Células Ganglionares de la Retina/citología , Células Ganglionares de la Retina/inmunologíaRESUMEN
Aquaporins (AQPs) are membrane proteins that facilitate water transport across biological membranes and are essential for the proper function of neural tissue. Although AQPs have been extensively studied in mammalian retina, their presence in lower vertebrate retina is less frequently characterized. AQP4 expressed in mammalian and chick Müller cells plays a major part in maintaining retinal homeostasis. In this study, we examined the immunoreactivity of AQP4 in the adult retina of gilthead sea bream (Sparus aurata-teleost fish), during light and dark adaptation. The AQP4 expression was detected in Müller cell somas at the inner nuclear layer and in the end-feet processes near the vitreoretinal border. Moreover, AQP4 was also evident in cone photoreceptor cells and in a GABAergic subpopulation of amacrine cells (AQP4-ACs). Four different types of AQP4-ACs were characterized based on their morphology and dendrite stratification. Interestingly, a stronger AQP4 immunoreactivity was observed in the inner nuclear layer during dark adaptation, accompanied by a significant increment in AQP4-ACs cell size. Hence, AQP4 may play an important role in water distribution in the teleost fish retina.
Asunto(s)
Células Amacrinas/metabolismo , Acuaporina 4/metabolismo , Peces/inmunología , Retina/metabolismo , Adaptación Ocular/fisiología , Células Amacrinas/citología , Células Amacrinas/inmunología , Animales , Acuaporina 4/fisiología , Agua Corporal/metabolismo , Forma de la Célula/fisiología , Adaptación a la Oscuridad/fisiología , Dendritas/metabolismo , Dendritas/ultraestructura , Ecosistema , Neuroglía/citología , Neuroglía/inmunología , Neuroglía/metabolismo , Retina/citología , Células Fotorreceptoras Retinianas Conos/citología , Células Fotorreceptoras Retinianas Conos/metabolismo , Especificidad de la Especie , Visión Ocular/fisiologíaRESUMEN
AII amacrine cells are critical interneurons in the rod pathway of mammalian retina, active primarily in dim lighting conditions. Melatonin, a neuromodulator produced at night in the retina, is believed to induce retinal adaptation to dim lighting conditions in most vertebrate species examined to date, including humans. We hypothesized that melatonin may influence retinal light adaptation by acting on AII cells directly and thus investigated whether melatonin receptors were expressed in AII neurons. Postmortem nonpathological eyes from four human donors as well as two eyes from two Macaque Fasicularis monkeys were analyzed. Double immunocytochemistry was performed using an anti-MT(1) antibody and an antibody to calretinin, an AII marker. Analysis utilized confocal microscopy. A polyclonal anti-calretinin antibody labelled amacrine cells exhibiting the distinct AII morphology, in both human and macaque retina. MT(1) immunoreactivity in macaque retina was similar to human staining, in that horizontal, amacrine and ganglion cell bodies were stained, as were inner segments of photoreceptors. In human retina 86% of calretinin positive cells expressed the MT(1) receptor peripherally, whereas centrally, 78% colocalization was observed. In the macaque retina, 100% of AII amacrine cells expressed MT(1) immunoreactivity both centrally and peripherally. That virtually all AII neurons express the MT(1) receptor in both human and macaque retina, may provide the first evidence demonstrating a role for melatonin in AII regulation, furthering the hypothesis of melatonin function in retinal light adaptation.