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Neurovascular Unit: A New Target for Treating Early Stages of Diabetic Retinopathy.

ABSTRACT: The concept of diabetic retinopathy as a microvascular disease has evolved and is now considered a more complex diabetic complication in which neurovascular unit impairment plays an essential role and, therefore, can be considered as a main therapeutic target in the early stages of the disease. However, neurodegeneration is not always the apparent primary event in the natural story of diabetic retinopathy, and a phenotyping characterization is recommendable to identify those patients in whom neuroprotective treatment might be of benefit. In recent years, a myriad of treatments based on neuroprotection have been tested in experimental models, but more interestingly, there are drugs with a dual activity (neuroprotective and vasculotropic). In this review, the recent evidence concerning the therapeutic approaches targeting neurovascular unit impairment will be presented, along with a critical review of the scientific gaps and problems which remain to be overcome before our knowledge can be transferred to clinical practice.

SUBMITTER: Simo R

PROVIDER: S-EPMC8399715 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Neurovascular Unit: A New Target for Treating Early Stages of Diabetic Retinopathy.

Simó Rafael R Simó-Servat Olga O Bogdanov Patricia P Hernández Cristina C

Pharmaceutics 20210823 8

The concept of diabetic retinopathy as a microvascular disease has evolved and is now considered a more complex diabetic complication in which neurovascular unit impairment plays an essential role and, therefore, can be considered as a main therapeutic target in the early stages of the disease. However, neurodegeneration is not always the apparent primary event in the natural story of diabetic retinopathy, and a phenotyping characterization is recommendable to identify those patients in whom neu ...[more]

PMID: 34452281

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Project description:Diabetic retinopathy (DR), one of the most common complications of diabetes mellitus, is characterized by degeneration of retinal neurons and neoangiogenesis. Until today, the pharmacological approaches for DR are limited and focused on counteracting the end-stage of this neurodegenerative disease, therefore efforts should be carried out to discover novel pharmacological targets useful to prevent DR development. Hyperglycemia is a major risk factor for endothelial dysfunction and vascular complication, which subsequently may trigger neurodegeneration. We previously demonstrated that, in the rat retina, hyperglycemia activates a new molecular cascade implicating, up-stream, protein kinase C βII (PKC βII), which in turn leads to a higher expression of vascular endothelial growth factor (VEGF), via the mRNA-binding Hu-antigen R (HuR) protein. VEGF is a pivotal mediator of neovascularization and a well-known vasopermeability factor. Blocking the increase of VEGF via modulation of this cascade can thus represent a new pharmacological option to prevent DR progression. To this aim, proper in vitro models are crucial for drug discovery, as they allow to better identify promising effective molecules. Considering that endothelial cells are key elements in DR and that hyperglycemia triggers the PKCβII/HuR/VEGF pathway, we set up two distinct in vitro models applying two different stimuli. Namely, human umbilical vein endothelial cells were exposed to phorbol 12-myristate 13-acetate, which mimics diacylglycerol whose synthesis is triggered by diabetic hyperglycemia, while human retinal endothelial cells were treated with high glucose for different times. After selecting the optimal experimental conditions able to determine an increased VEGF production, in search of molecules useful to prevent DR development, we investigated the capability of troxerutin, an antioxidant flavonoid, to counteract not only the rise of VEGF but also the activation of the PKCβII/HuR cascade in both in vitro models. The results show the capability of troxerutin to hinder the hyperglycemia-induced increase in VEGF in both models through PKCβII/HuR pathway modulation. Further, these data confirm the key engagement of this cascade as an early event triggered by hyperglycemia to promote VEGF expression. Finally, the present findings also suggest the potential use of troxerutin as a preventive treatment during the early phases of DR.

Project description:BackgroundPost-transplant diabetes mellitus (PTDM) is a specific subtype of diabetes with an uncertain impact on mortality and morbidity in post-transplant patients. Diabetic retinopathy is the most common microvascular complication of diabetes mellitus, but the long-term clinical progression in PTDM is unknown. New technologies are being used to assess pre-clinical signs of retinal changes, such as swept-source optical coherence tomography (OCT) and OCT-angiography. The aim of this study was to detect pre-clinical structural and vascular changes in the retina using swept-source-OCT and OCT-angiography in patients with PTDM.MethodsIn this retrospective cohort study, post-kidney transplant patients were divided into PTDM and non-PTDM (control) groups. Both eyes of eligible PTDM patients and controls were included in this study. Inner retinal layer thickness was measured with swept-source-OCT. Retinal capillary density and the foveal avascular zone were measured with OCT-angiography.ResultsIn the PTDM group, reduced thickness was found in the inferior ganglion cell layer plus inner plexiform layer (95% CI -8.76 to -0.68; p = 0.022) and the temporal inferior segment (95% CI -10.23 to -0.76; p = 0.024) of the inner retina, as well as in the retinal nerve fiber layer in the temporal (95% CI -34.78 to -9.28 p = 0.001) and temporal inferior segments (95% CI -33.26 to -5.03 p = 0.008). No significant differences were found in the vascular capillary plexus between groups at all depths, segments, or foveal avascular zone (p = 0.088).ConclusionsAccording to OCT-angiography, PTDM patients had reduced inner neurosensory retinal layers but no significant change in vascular density, which suggests that early neuroretinal degeneration might occur prior to vascular changes secondary to PTDM. Prospective studies could help elucidate the clinical course of retinal neuropathy and microvascular pathology in PTDM and provide a better understanding of PTDM complications.

Dataset Information

Neurovascular Unit: A New Target for Treating Early Stages of Diabetic Retinopathy.

Publications

Neurovascular Unit: A New Target for Treating Early Stages of Diabetic Retinopathy.

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