Degenerative changes of photoreceptors and pigment epithelium shown here prior to apoptotic loss of photoreceptors may contribute to functional alterations reported in diabetic human patients and different animal models, thus may serve as a potential model for testing the efficacy of neuroprotective agents in diabetes.
In diabetes, retinal dysfunctions exist prior to clinically detectable vasculopathy, however the pathology behind these functional deficits is still not fully established. Previously, our group published a detailed study on the retinal histopathology of type 1 diabetic (T1D) rat model, where specific alterations were detected. Although the majority of human diabetic patients have type 2 diabetes (T2D), similar studies on T2D models are practically absent. To fill this gap, we examined Zucker Diabetic Fatty (ZDF) rats - a model for T2D - by immunohistochemistry at the age of 32 weeks. Glial reactivity was observed in all diabetic specimens, accompanied by an increase in the number of microglia cells. Prominent outer segment degeneration was detectable with changes in cone opsin expression pattern, without a decrease in the number of labelled elements. The immunoreactivity of AII amacrine cells was markedly decreased and changes were detectable in the number and staining of some other amacrine cell subtypes, while most other cells examined did not show any major alterations. Overall, the retinal histology of ZDF rats shows a surprising similarity to T1D rats indicating that despite the different evolution of the disease, the neuroretinal cells affected are the same in both subtypes of diabetes.
Pituitary adenylate cyclase activating polypeptide (PACAP) is a member of the growing family of neurotrophic and neuroprotective factors playing important roles during neuronal development and protection against different types of injuries, such as Parkinson's disease, excitotoxicity, and ischemia. As shown with other neuronal tissues, we provide evidence that PACAP is protective in the retina against toxic injury induced by monosodium glutamate (MSG) in vivo. The need for characterization of its fragments and analogues has recently been emphasized. The aim of the present study was to compare the effects of the physiologically occurring fragments PACAP1-38 and 1-27 and the widely used antagonists (PACAP6-38 and 6-27) in retinal degeneration induced by MSG in neonatal pups. Histological analysis showed that MSG treatment caused the degeneration of the entire inner plexiform layer and the inner nuclear and ganglion cell layers seemed fused. The total thickness of the retina was significantly reduced. Similar and substantial protective effects could be observed after three treatments with PACAP1-38 and 1-27, while MSG toxicity was further aggravated by the PACAP antagonists PACAP6-38 and 6-27. Glutamate-induced toxicity is known to play a role in several retinal pathologies. Our results provide further evidence for the effectiveness of the endogenously present PACAP forms in counteracting retinotoxicity and call for further studies leading to the discovery of potent analogues that could be used in human ophthalmic diseases.
During the first postnatal weeks of the developing rodent retina, rhodopsin can be detected in a number of neuron-like cells in the inner retina. In the present study, we aim to characterize the morphology, number and staining characteristics of this peculiar population. Misplaced rhodopsin-positive cells (MRCs) were analyzed on retinas of four rodent species, labeled with various rhodopsin-specific antibodies. To investigate their possible relation with non-photoreceptor cells, sections were double-stained against distinct retinal cell types and proteins of the phototransduction cascade. The possibility of synapse formation and apoptosis were also investigated. In all species studied, misplaced cells comprised a few percent of all rhodopsin-positive elements. This ratio declined from the end of the second week and MRCs disappeared nearly completely from the retina by P24. MRCs resembled resident neurons of the inner retina, while outer segment-like processes were seen only rarely. MRCs expressed no other photopigment types and showed no colocalization with any of the bipolar, horizontal, amacrine and ganglion cell markers used. While all MRCs colabeled for arrestin and recoverin, other proteins of the phototransduction cascade were only detectable in a minority of the population. Only a few MRCs were shown to form synaptic-like endings. Our results showed that, during development, some rhodopsin-expressing cells are displaced to the inner retinal layers. Although most MRCs lack morphological features of photoreceptors, they contain some but not all, elements of the phototransduction cascade, indicating that they are most probably misplaced rods that failed to complete differentiation and integrate into the photoreceptor mosaic.
The purpose of this work was to evaluate a potentially useful animal model, Meriones shawi (M.sh)-developing metabolic X syndrome, diabetes and possessing a visual streak similar to human macula-in the study of diabetic retinopathy and diabetic macular edema (DME). Type 2 diabetes (T2D) was induced by high fat diet administration in M.sh. Body weights, blood glucose levels were monitored throughout the study. Diabetic retinal histopathology was evaluated 3 and 7 months after diabetes induction. Retinal thickness was measured, retinal cell types were labeled by immunohistochemistry and the number of stained elements were quantified. Apoptosis was determined with TUNEL assay. T2D induced progressive changes in retinal histology. A significant decrease of retinal thickness and glial reactivity was observed without an increase in apoptosis rate. Photoreceptor outer segment degeneration was evident, with a significant decrease in the number of all cones and M-cone subtype, but-surprisingly-an increase in S-cones. Damage of the pigment epithelium was also confirmed. A decrease in the number and labeling intensity of parvalbumin- and calretinin-positive amacrine cells and a loss of ganglion cells was detected. Other cell types showed no evident alterations. No DME-like condition was noticed even after 7 months. M.sh could be a useful model to study the evolution of diabetic retinal pathology and to identify the role of hypertension and dyslipidemia in the development of the reported alterations. Longer follow up would be needed to evaluate the potential use of the visual streak in modeling human macular diseases.
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