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

Simó, Rafael; Simó‐Servat, Olga; Bogdanov, Patricia; Hernández, Cristina

doi:10.3390/pharmaceutics13081320

Cited by 38 publications

(52 citation statements)

References 212 publications

(272 reference statements)

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“…We found a downregulation (protein and mRNA levels) of several presynaptic proteins such as synapsin I ( Figure 1 ), synaptophysin ( Figure 2 ), synaptotagmin ( Figure 3 ), syntaxin 1A ( Figure 4 ), vesicle-associated membrane protein 2 (VAMP2) ( Figure 5 ), and synaptosomal-associated protein of 25 kDa (SNAP25) ( Figure 6 ) in db/db mice treated with vehicle in comparison with non-diabetic mice. All these presynaptic proteins are involved in vesicle biogenesis, mobilization and docking, membrane fusion and recycling, and synaptic neurotransmission [ 15 ].…”

Section: Resultsmentioning

confidence: 99%

Neuromodulation Induced by Sitagliptin: A New Strategy for Treating Diabetic Retinopathy

et al. 2021

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Diabetic retinopathy (DR) involves progressive neurovascular degeneration of the retina. Reduction in synaptic protein expression has been observed in retinas from several diabetic animal models and human retinas. We previously reported that the topical administration (eye drops) of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, prevented retinal neurodegeneration induced by diabetes in db/db mice. The aim of the present study is to examine whether the modulation of presynaptic proteins is a mechanism involved in the neuroprotective effect of sitagliptin. For this purpose, 12 db/db mice, aged 12 weeks, received a topical administration of sitagliptin (5 μL; concentration: 10 mg/mL) twice per day for 2 weeks, while other 12 db/db mice were treated with vehicle (5 μL). Twelve non-diabetic mice (db/+) were used as a control group. Protein levels were assessed by western blot and immunohistochemistry (IHC), and mRNA levels were evaluated by reverse transcription polymerase chain reaction (RT-PCR). Our results revealed a downregulation (protein and mRNA levels) of several presynaptic proteins such as synapsin I (Syn1), synaptophysin (Syp), synaptotagmin (Syt1), syntaxin 1A (Stx1a), vesicle-associated membrane protein 2 (Vamp2), and synaptosomal-associated protein of 25 kDa (Snap25) in diabetic mice treated with vehicle in comparison with non-diabetic mice. These proteins are involved in vesicle biogenesis, mobilization and docking, membrane fusion and recycling, and synaptic neurotransmission. Sitagliptin was able to significantly prevent the downregulation of all these proteins. We conclude that sitagliptin exerts beneficial effects in the retinas of db/db mice by preventing the downregulation of crucial presynaptic proteins. These neuroprotective effects open a new avenue for treating DR as well other retinal diseases in which neurodegeneration/synaptic abnormalities play a relevant role.

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Section: Resultsmentioning

confidence: 99%

Neuromodulation Induced by Sitagliptin: A New Strategy for Treating Diabetic Retinopathy

et al. 2021

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“…Besides the tight control of blood glucose level, a good control of hypertension is also an important step during the clinical management of DR, because they usually occur together in clinical practice and have a reciprocal connection. Among their cellular and molecular processes, we could find several common, connected impairment mechanisms, such as neurodegeneration, loss of synaptic connectivity, glial activation or the neurovascular unit dysfunction [ 18 , 19 , 23 , 24 ], which provide explanations for the tight relationship between them. Research into their pharmacological management have elucidated their complicated, interwoven processes and have initiated the need to develop new combined therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

A Promising Combination: PACAP and PARP Inhibitor Have Therapeutic Potential in Models of Diabetic and Hypertensive Retinopathies

Pöstyéni

Szabadfi

Sétáló

et al. 2021

Cells

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Diabetes and hypertension are complex pathologies with increasing prevalence nowadays. Their interconnected pathways are frequently manifested in retinopathies. Severe retinal consequences and their tight connections as well as their possible treatments are particularly important to retinal research. In the present, work we induced diabetes with streptozotocin in spontaneously hypertensive rats and treated them either with PACAP or olaparib and alternatively with both agents. Morphological and immunohistochemical analyses were carried out to describe cell-specific changes during pathologies and after different treatments. Diabetes and hypertension caused massive structural and cellular changes especially when they were elicited together. Hypertension was crucial in the formation of ONL and OPL damage while diabetes caused significant differences in retinal thickness, OPL thickness and in the cell number of the GCL. In diabetes, double neuroprotective treatment ameliorated changes of calbindin-positive cells, rod bipolar cells and dopaminergic amacrine cells. Double treatment was curative in hypertensive diabetic rat retinas, especially in the case of rod bipolar and parvalbumin-positive cells compared to untreated or single-treated retinas. Our results highlighted the promising therapeutic benefits of olaparib and PACAP in these severe metabolic retinal disorders.

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“…The developing understanding of the neurovascular interactions in health and disease is guiding efforts to find novel therapeutic targets capable of arresting DR at early stages (Simo et al, 2021). Strategies for promoting tissue repair and preventing neuroinflammation have shown promising results in the treatment of neurovascular diabetic complications.…”

Section: The Needmentioning

confidence: 99%

Novel Therapeutics for Diabetic Retinopathy and Diabetic Macular Edema: A Pathophysiologic Perspective

2022

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Diabetic retinopathy (DR) and diabetic macular edema (DME) are retinal complications of diabetes that can lead to loss of vision and impaired quality of life. The current gold standard therapies for treatment of DR and DME focus on advanced disease, are invasive, expensive, and can trigger adverse side-effects, necessitating the development of more effective, affordable, and accessible therapies that can target early stage disease. The pathogenesis and pathophysiology of DR is complex and multifactorial, involving the interplay between the effects of hyperglycemia, hyperlipidemia, hypoxia, and production of reactive oxygen species (ROS) in the promotion of neurovascular dysfunction and immune cell polarization to a proinflammatory state. The pathophysiology of DR provides several therapeutic targets that have the potential to attenuate disease progression. Current novel DR and DME therapies under investigation include erythropoietin-derived peptides, inducers of antioxidant gene expression, activators of nitric oxide/cyclic GMP signaling pathways, and manipulation of arginase activity. This review aims to aid understanding of DR and DME pathophysiology and explore novel therapies that capitalize on our knowledge of these diabetic retinal complications.

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

Cited by 38 publications

References 212 publications

Neuromodulation Induced by Sitagliptin: A New Strategy for Treating Diabetic Retinopathy

Neuromodulation Induced by Sitagliptin: A New Strategy for Treating Diabetic Retinopathy

A Promising Combination: PACAP and PARP Inhibitor Have Therapeutic Potential in Models of Diabetic and Hypertensive Retinopathies

Novel Therapeutics for Diabetic Retinopathy and Diabetic Macular Edema: A Pathophysiologic Perspective

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