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Mechanisms involved in the beneficial effects of CaD exerts in DR. The red arrows represents the vasculotropic actions and the black arrows the neuroprotective actions. CaD: Calcium dobesilate monohydrate; DR: diabetic retinopathy; ET-1: endothelin-1;VEGF: vascular endothelial growth factor.
Citations
... Two randomized placebo-controlled trials demonstrated the effectiveness of CaD in preventing the progression of early-stage DR [47,48], but its effectiveness in AEDR remains to be determined. As occurs with fenofibrate, CaD targets multiple pathogenic pathways involved in DR [49]. However, further research to better understand the mechanisms of action and more targeted clinical trials are needed. ...
Diabetic retinopathy (DR) is the leading cause of preventable blindness in the working-age population. The disease progresses slowly, and we can roughly differentiate two stages: early-stage (ESDR), in which there are mild retinal lesions and visual acuity is generally preserved, and advanced-stage (ASDR), in which the structural lesions are significant and visual acuity is compromised. At present, there are no specific treatments for ESDR and the current recommended action is to optimize metabolic control and maintain close control of blood pressure. However, in the coming years, it is foreseeable that therapeutic strategies based in neuroprotection will be introduced in the clinical arena. This means that screening aimed at identifying patients in whom neuroprotective treatment might be beneficial will be crucial. Regarding the treatment of ASDR, the current primary course is based on laser photocoagulation and intravitreal injections of anti-angiogenic factors or corticosteroids. Repeated intravitreal injections of anti-VEGF agents as the first-line treatment would be replaced by more cost-effective and personalized treatments based on the results of “liquid biopsies” of aqueous humor. Finally, topical administration (i.e., eye drops) of neuroprotective, anti-inflammatory and anti-angiogenic agents will represent a revolution in the treatment of DR in the coming decade. In this article, all these approaches and others will be critically discussed from a holistic perspective.
... Two drugs, fenofibrate and calcium dobesilate, administered by oral route have provided effectiveness in preventing neurodegeneration by targeting various pathways simultaneously. 24,63,[70][71][72][73] The neuroprotection conferred by peptides in retinal disease has been recently comprehensively reviewed by Cervia et al. 74 Nutraceuticals can also exert this multipathway effect and their beneficial effects in DR-related models have been recently and extensively reviewed. 75 Recent research showing the downregulation of several proteins synthesized by the retina with neurotrophic activity, such as pigment epithelium-derived factor, somatostatin, and glucagon-like peptide 1 (GLP-1), have pointed to their replacement as a reasonable approach for preventing retinal neurodegeneration. ...
Retinal neurodegeneration plays a significant role in the pathogenesis of diabetic retinopathy, the leading cause of preventable blindness. The hallmarks of diabetes-induced neurodegeneration are neural cell apoptosis and glial activation, which seem even before vascular lesions can be detected by ophthalmoscopic examination. The molecular mediators of retinal neurodegeneration include proinflamma- tory cytokines, oxidative stress, mitochondrial dysfunction, and the molecular pathways closely related to chronic hyperglycemia. In this article, an overview of the main components of neurodegeneration, its key underlying mechanisms, and the more useful experimental models for investigative purposes will be given. In addition, the results of most relevant treatments based on neuroprotection, and the research gaps that should be filled will be critically reviewed.
... The poor understanding of its mechanisms of action has been one of the reasons for this. However, in recent years, experimental evidence has shown that CaD exerts a multifaceted action on neurovascular unit impairment, thus supporting the observed beneficial effects in the early stages of DR [51]. These pleiotropic effects include anti-inflammatory, anti-apoptotic, and antioxidant actions in both neuroretina and microvessels, thus ameliorating the disruption of the blood-retinal barrier (BRB) and the vascular leakage [52][53][54][55]. ...
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.
... Under physiological conditions, CaD does not cross the blood barriers of the body. However, as demonstrated in diabetic retinopathy [30], the retina blood barrier breakdown allows the entry of CaD, which protects retina neurons [49]. Although we did not assess the permeability of BBB in our experimental conditions, increased blood-brain barrier permeability in D-gal-treated mice [47] might allow the entry of CaD. ...
The long-term treatment of mice with D-galactose (D-gal) induces the overproduction of reactive oxygen species (ROS) and is a well-accepted experimental model of oxidative stress-linked cognitive disorders in physiological aging. Calcium dobesilate (CaD, Doxium®) is an established vasoactive and angioprotective drug commonly used for the clinical treatment of diabetic retinopathy and chronic venous insufficiency. It has antioxidant properties and controls vascular permeability. In the current study, we evaluated the protective effects of CaD (50 and 100 mg/kg/day p.o.) in male mice treated with D-gal (500 mg/kg/day p.o.) for six weeks. Results demonstrated that body weight loss, anxiety-like and cognitive impairments of D-gal-treated animals were reversed by CaD administration as evaluated by the measurement of mice performance in elevated plus-maze, Y-maze, and shuttle box tests. CaD treatment also inhibited the oxidative stress in aging mouse brains by decreasing malondialdehyde (MDA) levels and increasing superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) enzyme activities. These results could open new perspectives for the clinical use of CaD in treating and preventing cognitive impairment in older people.
... VEGF-was considered to associate with oxidative stress and inflammatory response and induce retinal neovascularization, vascular leakage, and macular edema [51][52][53]. Additionally, the effect of CaD on VEGF-was confirmed by other researches [54,55], but FSM probably revealed better effects, at least according to the PCR and western blot results in our research. Our results presented that the compound traditional Chinese medicine FSM could downregulate the expression of VEGFto depress angiogenesis of DR, which may provide a new option or supplement for patients. ...
Aims:
Diabetic retinopathy (DR) remains one of the leading causes of acquired blindness. Fushiming capsule (FSM), a compound traditional Chinese medicine, is clinically used for DR treatment in China. The present study was to investigate the effect of FSM on retinal alterations, inflammatory response, and oxidative stress triggered by diabetes.
Main methods:
Diabetic rat model was induced by 6-week high-fat and high-sugar diet combined with 35 mg/kg streptozotocin (STZ). 30 days after successful establishment of diabetic rat model, full field electroretinography (ffERG) and optical coherence tomography (OCT) were performed to detect retinal pathological alterations. Then, FSM was administered to diabetic rats at different dosages for 42-day treatment and diabetic rats treated with Calcium dobesilate (CaD) capsule served as the positive group. Retinal function and structure were observed, and retinal vascular endothelial growth factor-α (VEGF-α), glial fibrillary acidic (GFAP), and vascular cell adhesion protein-1 (VCAM-1) expressions were measured both on mRNA and protein levels, and a series of blood metabolic indicators were also assessed.
Key findings:
In DR rats, FSM (1.0 g/kg and 0.5 g/kg) treatment significantly restored retinal function (a higher amplitude of b-wave in dark-adaptation 3.0 and OPs2 wave) and prevented the decrease of retinal thickness including inner nuclear layer (INL), outer nuclear layer (ONL), and entire retina. Additionally, FSM dramatically decreased VEGF-α, GFAP, and VCAM-1 expressions in retinal tissues. Moreover, FSM notably improved serum antioxidative enzymes glutathione peroxidase, superoxide dismutase, and catalase activities, whereas it reduced serum advanced glycation end products, methane dicarboxylic aldehyde, nitric oxide, and total cholesterol and triglycerides levels.
Significance:
FSM could ameliorate diabetic rat retina damage possibly via inhibiting inflammation and improving antioxidation.
... К настоящему времени накоплена определенная доказательная база по применению синте тического ангиопротектора -добезилата кальция (ДК) ДоксиХема (Сербия) при различных заболеваниях, со провождающихся нарушением сосудистой проницаемости и микроциркуляции, в т. ч. при диабетических микроангио патиях. ДК зарекомендовал себя как препарат, улучшаю щий прогноз при ДР и ДН [25, 26,29,30]. ...
Diabetic microangiopathies: mechanisms of development, approaches to the therapy
Birukova E.V.1, Shinkin M.V.2
1 A.I. Yevdokimov Moscow State University of Medicine and Dentistry
2 The Loginov Moscow Clinical Scientific Center
Diabetes mellitus of the first and second type is a chronic disease associated with the development of vascular complications, the prevention of which is one of the most important tasks of modern medicine. The mechanisms of development of diabetic angiopathy are complex and diverse.
Diabetic retinopathy (DR) is one of the most common and severe microvascular complications of diabetes, which leads to impaired vision and, in the future, blindness. DR is diagnosed in almost all the patients with type 1 diabetes and in 60% of patients with type 2 diabetes with a duration of the disease of more than 20 years.
Diabetic nephropathy is responsible for 40-50% of all cases of end-stage renal disease. Among patients with type 1 diabetes mellitus, one-third have serious kidney complications, characterized by an increase in urinary albumin excretion and a decrease in renal function, up to hemodialysis.
Therapeutic approaches to the treatment of microangiopathies (diabetic retinopathy and diabetic nephropathy), the use of calcium dobesilate are discussed.
Calcium dobesilate refers to the pharmacological group of angioprotectors and microcirculatory correctors.
Key words: diabetes mellitus, microangiopathy, diabetic nephropathy, diabetic retinopathy, developmental mechanisms, treatment, calcium dobesilate.
For citation: Birukova E.V., Shinkin M.V. Diabetic microangiopathies: mechanisms of development, approaches to the therapy. RMJ “Clinical ophthalmology”. 2018;2:91–96.
Introduction
Vascular endothelial growth factor (VEGF) plays an essential role in development of diabetic macular edema (DME). While there is evidence suggesting that silymarin, a flavonoid extracted from Silybum marianum, could be useful for prevention and treatment of diabetic nephropathy, no studies have been conducted in diabetic retinopathy (DR). The aim of this study was to assess the effect of silymarin on disruption of inner blood retinal barrier (BRB), the primary cause of DME.
Materials and methods
Human retinal endothelial cells (HRECs) were cultured under standard (5.5 mM D-glucose) and diabetogenic conditions (25 mM D-glucose and 25 mM D-glucose + recombinant vascular endothelial growth factor [rVEGF, 25 mg/mL]). To assess cell viability, three concentrations of silymarin were tested (2, 4 and 10 μg/mL). The effect of silymarin on HREC disruption was determined using a dextran (70 kD) permeability asssay.
Results
No differences were found in the viability of HRECs treated with 2 or 4 μg/mL of silymarin as compared to untreated cells, but viability significantly decreased after using 10 μg/mL. The concentration of 4 μg/mL was therefore selected. Silymarin (4 μg/mL) caused a significant decrease in VEGF-induced permeability in both media with 5.5 nM (422±58 vs. 600±72 ng/mL/cm2; p<0.03) and 25 nM of D-glucose (354 ± 28 vs. 567 ± 102 ng/mL/cm2; p<0.04).
Discussion
Our results show that silymarin is effective for preventing hyperpermeability induced by diabetic conditions in HRECs. Further studies are needed to assess whether silymarin could be useful to treat DME.
Introduction:
Vascular endothelial growth factor (VEGF) plays an essential role in development of diabetic macular edema (DME). While there is evidence suggesting that silymarin, a flavonoid extracted from Silybum marianum, could be useful for prevention and treatment of diabetic nephropathy, no studies have been conducted in diabetic retinopathy (DR). The aim of this study was to assess the effect of silymarin on disruption of inner blood retinal barrier (BRB), the primary cause of DME.
Materials and methods:
Human retinal endothelial cells (HRECs) were cultured under standard (5.5mM D-glucose) and diabetogenic conditions (25mM D-glucose and 25mM D-glucose + recombinant vascular endothelial growth factor [rVEGF, 25mg/mL]). To assess cell viability, three concentrations of silymarin were tested (2, 4 and 10μg/mL). The effect of silymarin on HREC disruption was determined using a dextran (70kD) permeability asssay.
Results:
No differences were found in the viability of HRECs treated with 2 or 4μg/mL of silymarin as compared to untreated cells, but viability significantly decreased after using 10μg/mL. The concentration of 4 μg/mL was therefore selected. Silymarin (4μg/mL) caused a significant decrease in VEGF-induced permeability in both media with 5.5nM (422±58 vs. 600±72 ng/mL/cm2; p<0.03) and 25nM of D-glucose (354 ± 28 vs. 567 ± 102 ng/mL/cm2; p<0.04).
Discussion:
Our results show that silymarin is effective for preventing hyperpermeability induced by diabetic conditions in HRECs. Further studies are needed to assess whether silymarin could be useful to treat DME.
