Reduction of retinal albumin leakage by the antioxidant calcium dobesilate in streptozotocin-diabetic rats

Rota, Rossella; Chiavaroli, Carlo; Garay, Ricardo P.; Hannaert, Patrick

doi:10.1016/j.ejphar.2004.05.019

Cited by 59 publications

(51 citation statements)

References 43 publications

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“…This is an important issue due to the pivotal role of oxidative stress in the pathogenesis of DR. 47 It has been reported that CaD protects against BRB leakage, and this effect was correlated with a decrease in the levels of VEGF in the retina. 16 In the present study, we have confirmed these results.…”

Section: Discussionsupporting

confidence: 82%

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Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

Solà-Adell

Bogdanov

Hernández

et al. 2017

Current Eye Research

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Purpose: The mechanisms involved in the reported beneficial effects of Calcium dobesilate monohydrate (CaD) for the treatment of diabetic retinopathy (DR) remain to be elucidated. The main aim of the present study is to examine whether CaD prevents early events in the pathogenesis of DR such as neurodegeneration and vascular leakage. In addition, putative mediators of both neurodegeneration (glutamate/GLAST, ET-1/ETB receptor) and early microvascular impairment (ET-1/ETA receptor, oxidative stress, VEGF, and the PKC-delta-p38 MAPK pathway) have been examined. Methods: Diabetic (db/db) mice were randomly assigned to daily oral treatment with CaD (200 mg/Kg/ day) (n = 12) or vehicle (n = 12) for 14 days. In addition, 12 non-diabetic (db/+) mice matched by age were used as the control group. Functional abnormalities were assessed by electroretinography. Neurodegeneration and microvascular abnormalities were evaluated by immunohistochemistry and Western blot. Glutamate was determined by HPLC. Results: CaD significantly decreased glial activation and apoptosis and produced a significant improvement in the electroretinogram parameters. Mechanistically, CaD prevented the diabetes-induced upregulation of ET-1 and its cognate receptors (ETA-R and ETB-R), which are involved in microvascular impairment and neurodegeneration, respectively. In addition, treatment with CaD downregulated GLAST, the main glutamate transporter, and accordingly prevented the increase in glutamate. Finally, CaD prevented oxidative stress, and the upregulation of VEGF and PKC delta-p38 MAPK pathway induced by diabetes, thus resulting in a significant reduction in vascular leakage.Conclusions: Our findings demonstrate for the first time that CaD exerts neuroprotection in an experimental model of DR. In addition, we provide first evidence that CaD prevents the overexpression of ET-1 and its receptors in the diabetic retina. These beneficial effects on the neurovascular unit could pave the way for clinical trials addressed to confirm the effectiveness of CaD in very early stages of DR. ARTICLE HISTORY

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Section: Discussionsupporting

confidence: 82%

“…4,16,27 Blood glucose (Optium. Abbot, Berkshire, UK) levels and body weight were measured at baseline and weekly.…”

Section: Interventional Studymentioning

confidence: 99%

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

Solà-Adell

Bogdanov

Hernández

et al. 2017

Current Eye Research

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“…However, an MDA concentration in systemic blood may reflect changes unrelated to the cardiac oxidative stress (prostanoid synthesis) activity of aldehyde-dehydrogenase and aldose reductase [23][24][25]. Despite calcium dobesilate therapy, an increase in erythrocyte and plasma MDA levels and a decrease in erythrocyte GSH in the present study shows that calcium dobesilate is not an effective antioxidant, which is in contrast to the studies that have demonstrated its antioxidant properties [26].…”

Section: Discussioncontrasting

confidence: 56%

Calcium dobesilate may improve hemorheology in patients undergoing coronary artery bypass grafting

Beşirli

Aydemir

Arslan

et al. 2012

Rev Bras Cir Cardiovasc

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Dobesilato de cálcio pode melhorar hemorreologia em pacientes submetidos à cirurgia de revascularização miocárdicaCalcium dobesilate may improve hemorheology in patients undergoing coronary artery bypass grafting Abstract Background: Calcium dobesilate is an angioprotective agent that has positive effects on hemorheological parameters. It is an antioxidant that increases endothelialderived vasodilator substance secretion, there are none that analyze its effects during the postoperative period of patients undergoing myocardial revascularization.Objective: We aimed to determine the effects of calcium dobesilate on hemorheological parameters, such as reduced glutathione and malondialdehyde in patients with ischemic heart disease undergoing myocardial revascularization in the postoperative period.Methods: One hundred and thirty-four patients operated for coronary heart disease were included in this study. Hemorheological, oxidant and antioxidant parameters were measured two days after surgery and after a period of treatment with calcium dobesilate. Then, 500 mg of calcium dobesilate was given twice a day to one group of 68 patients for three months. The control group was composed of 66 patients who did not receive this medication.Results: The increase in the erythrocyte deformability index was found to be significant compared with both the pretreatment values and with the 1 st and 2 nd values of the control group after calcium dobesilate administration, whereas there were no significant changes in blood viscosity, glutathione (GSH) or malondialdehyde (MDA) values after the calcium dobesilate administration. The same improvement in the CCS class was observed in patients regardless of they received the calcium dobesilate treatment.Conclusion: In the present investigation, the same improvement in the CCS class was observed in patients regardless of they received the calcium dobesilate treatment. Improvements with calcium dobesilate were statistically significant only in the increase in erythrocyte flexibility.Descriptors: Coronary artery disease. Atherosclerosis. Coronary artery bypass. ResumoAntecedentes: O dobesilato de cálcio é um agente angioprotetor que tem efeitos positivos sobre os parâmetros hemorreológicos. É um antioxidante que aumenta a secreção endotelial derivada da substância vasodilatadora, não há nada que analisar os seus efeitos durante o período pós-operatório de pacientes submetidos a revascularização do miocárdio.Objetivo: Nosso objetivo foi determinar os efeitos de dobesilato de cálcio sobre os parâmetros hemorreológicos, tais como glutationa reduzida e malondialdeído em pacientes com doença cardíaca isquêmica submetidos a revascularização do miocárdio no pós-operatório. RBCCV 44205-1379

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“…Like increased AR activity, it has been implicated in increased vascular permeability, leucostasis, accelerated retinal vascular cell apoptosis, formation of acellular capillaries and VEGF overexpression, as well as basement membrane thickening [7,9,10,18,34,35]. Antioxidant treatment prevented or alleviated leucocyte adhesion to endothelial cells [7], VEGF overexpression [9,36], increased vascular permeability [36], retinal cell apoptosis [18], basement membrane thickening [35] and formation of acellular capillaries [10,18] in the retina of diabetic rats. In our study, mice with short-term STZ diabetes did not have evidence of enhanced retinal lipid peroxidation.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, tissue-specific overexpression or knock-down of specific genes creates the possibility of exploring the role of vascular and non-vascular mechanisms in the pathogenesis of diabetic retinopathy. Whereas the presence of such phenomena as sorbitol pathway hyperactivity [3,4,14], NAD + /NADH redox imbalances [15,16], oxidative-nitrosative stress [6,[17][18][19], vascular endothelial growth factor (VEGF) overexpression [9,14,20,21], and, recently, PARP activation [11,19,21], is well documented in the diabetic rat retina, the corresponding information in diabetic mice is scarce and often based on single-source data [22]. The primary goal of this study was to compare early biochemical changes in diabetic rats and mice with similar (6-week) durations of streptozotocin (STZ)-induced diabetes.…”

Section: Introductionmentioning

confidence: 99%

Early diabetes-induced biochemical changes in the retina: comparison of rat and mouse models

et al. 2006

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Aims/hypothesis Recently, various transgenic and knockout mouse models have become available for studying the pathogenesis of diabetic retinopathy. At the same time, diabetes-induced retinal changes in the wild-type mice remain poorly characterised. The present study compared retinal biochemical changes in rats and mice with similar (6-week) durations of streptozotocin-induced diabetes. Materials and methods The experiments were performed on Wistar rats and C57Bl6/J mice. Retinal glucose, sorbitol, fructose, lactate, pyruvate, glutamate, α-ketoglutarate and ammonia were measured spectrofluorometrically by enzymatic methods. Vascular endothelial growth factor (VEGF) protein was assessed by ELISA, and poly(ADP-ribosyl)ation by immunohistochemistry and western blot analysis. Free mitochondrial and cytosolic NAD + /NADH ratios were calculated from the glutamate and lactate dehydrogenase systems. Results Retinal glucose concentrations were similarly increased in diabetic rats and mice, vs controls. Diabetic rats manifested ∼26-and 5-fold accumulation of retinal sorbitol and fructose, respectively, whereas elevation of both metabolites in diabetic mice was quite modest. Correspondingly, diabetic rats had (1) increased retinal malondialdehyde plus 4-hydroxyalkenal concentrations, (2) reduced superoxide dismutase (SOD), glutathione peroxidase, glutathione reductase and glutathione transferase activities, (3) slightly increased poly(ADP-ribose) immunoreactivity and poly(ADP-ribosyl)ated protein abundance, and (4) VEGF protein overexpression. Diabetic mice lacked these changes. SOD activity was 21-fold higher in murine than in rat retinas (the difference increased to 54-fold under diabetic conditions), whereas other antioxidative enzyme activities were 3-to 10-fold lower. With the exception of catalase, the key antioxidant defence enzyme activities were increased, rather than reduced, in diabetic mice. Diabetic rats had decreased free mitochondrial and cytosolic NAD + / NADH ratios, consistent with retinal hypoxia, whereas both ratios remained in the normal range in diabetic mice. Conclusions/interpretation Mice with short-term streptozotocin-induced diabetes lack many biochemical changes that are clearly manifest in the retina of streptozotocin-diabetic rats. This should be considered when selecting animal models for studying early retinal pathology associated with diabetes.

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Reduction of retinal albumin leakage by the antioxidant calcium dobesilate in streptozotocin-diabetic rats

Cited by 59 publications

References 43 publications

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

Calcium dobesilate may improve hemorheology in patients undergoing coronary artery bypass grafting

Early diabetes-induced biochemical changes in the retina: comparison of rat and mouse models

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