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Resumen de Neurodegeneration and inflammation: two crucial pathogenic events in diabetic retinopathy. New experimental insights and clinical perspectives

Olga Simó Servat

  • Neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR). In fact, the American Diabetes Association has recently defined DR as a highly tissue-specific neurovascular complication, thus emphasizing the importance of the neurovascular unit in the development of DR. The retina is a brain-derived tissue and there is growing evidence indicating that type 2 diabetic subjects are more prone to develop neurodegenerative processes such as Alzheimer’s disease. Therefore, it seems reasonable to postulate that the mediators of the neurodegenerative process that occurs in the brain could also be present in the diabetic retina. On this basis, the general objective of this thesis is to investigate the relationship between retinal and brain neurodegeneration and its potential clinical and therapeutic implications.

    The first part of this thesis focuses on experimental studies addressed to identifying mediators of impairment of the neurovascular unit. For this purpose a proteomic “hypothesis-free” study was performed comparing human retinas from non-diabetic and diabetic donors with and without glial activation (one of the hallmarks of retinal neurodegeneration). The Ingenuity Pathway Analysis revealed that several critical pathways related to brain neurodegenerative diseases were differently expressed in retinas from diabetic patients and in particular in those with glial activation. This observation supports the concept that a common soil exists in the neurodegenerative processes that occur in the retina and the brain. In addition, a downregulation of several proteins involved in axonal transport and the cytoskeleton was found in retinas from diabetic donors with glial activation. Furthermore, diabetes-induced glial activation was associated with a dysregulation of the complement system, as well as an upregulation of the proteins that govern the cytoskeleton changes. These results were confirmed by orthogonal methods. These novel findings contribute not only to our understanding of the mechanisms involved in the vascular leakage induced by neurovascular unit impairment, but could also have potential therapeutic implications.

    The second part of this doctoral thesis is based on a “driven hypothesis” aimed at examining whether endothelin-1 plays a pivotal role in the neurovascular unit impairment that occurs in DR. This is based on the fact that by means of ETA receptors ET-1 leads to vascular damage and through ETB induces neurodegeneration. We first found an overexpression of both ET-1 and its receptors (ETA and ETB) in the retinas from diabetic donors in comparison with non-diabetic donors. Second, we found that topical administration of bosentan (a blocker of ETA and ETB receptors) prevented retinal neurodegeneration induced by diabetes in the db/db mouse model. In addition, the inhibition of diabetes-induced upregulation of PKC-β, TNF-α and VEGF plays an important role in the beneficial vascular action of bosentan. These dual beneficial effects of bosentan (neurotrophic and vasculotropic) and the pharmacokinetic results point to this drug as an excellent candidate to be tested in clinical trials. The third part of the thesis is a clinical study addressed to reinforcing the concept that the assessment of retinal neurodegeneration could be a useful tool to identify those diabetic subjects at risk of developing dementia. Indeed, in a previous study we demonstrated that retinal sensitivity assessed by fundus-driven microperimetry was related to brain neurodegeneration and could be a useful biomarker for identifying patients with T2D who are at risk of developing Alzheimer’s disease. In the present work, we assessed whether gaze fixation, a parameter that can also be assessed by retinal microperimetry, is associated with cognitive impairment. This is based on previous evidence indicating that the capacity to maintain visual gaze on a single location (fixation) is hampered in Alzheimer’s disease. Our results showed that gaze fixation is more unstable as cognitive impairment progresses. Moreover the assessment of fixational parameters significantly improves retinal sensitivity assessment in differentiating those subjects with mild cognitive impairment from normocognitive diabetic subjects. Therefore, the measurement of retinal sensitivity in combination with parameters of fixation by using microperimetry could be a reliable method for detecting prodromal stages of dementia in the T2D population. Hopefully, these findings will be the proof of concept of a large scale-clinical study.

    Overall, this work contributes to the knowledge of the mediators of neurovascular unit impairment in the early stages of DR and increases our understanding of the link between retinal and brain neurodegeneration in the setting of the type 2 diabetic population. In addition, our findings suggest further candidates as new potential targets for the treatment of DR.


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