Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

Autor: Cristina Hernández, Rafael Simó, Cristina Solà-Adell, Marta Valeri, Marta García-Ramírez, Joel Sampedro, Patricia Bogdanov, Christian Pasquali
Rok vydání: 2017
Předmět:
0301 basic medicine
MAPK/ERK pathway
Male
Vascular Endothelial Growth Factor A
medicine.medical_specialty
Cell Survival
Blotting
Western
Calcium dobesilate
Apoptosis
Enzyme-Linked Immunosorbent Assay
Retinal Pigment Epithelium
medicine.disease_cause
Calcium Dobesilate
Real-Time Polymerase Chain Reaction
Hemostatics
Retina
Diabetes Mellitus
Experimental
Pathogenesis
03 medical and health sciences
Cellular and Molecular Neuroscience
Mice
0302 clinical medicine
Internal medicine
medicine
Electroretinography
In Situ Nick-End Labeling
Animals
Humans
Cells
Cultured
Diabetic Retinopathy
business.industry
Neurodegeneration
Glutamate receptor
Diabetic retinopathy
medicine.disease
Sensory Systems
Ophthalmology
Vascular endothelial growth factor A
Oxidative Stress
030104 developmental biology
Endocrinology
Diabetes Mellitus
Type 2
Gene Expression Regulation
Microscopy
Fluorescence
030221 ophthalmology & optometry
RNA
business
Oxidative stress
medicine.drug
Zdroj: Current eye research. 42(9)
ISSN: 1460-2202
Popis: 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.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.CaD significantly decreased glial activation and apoptosis and produced a significant improvement in the electroretinogram parameters. Mechanistically, CaD prevented the diabetes-induced up-regulation 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.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.
Databáze: OpenAIRE
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