Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

Cristina Solà-Adell, Patricia Bogdanov, Cristina Hernández, Joel Sampedro, Marta Valeri, Marta Garcia-Ramirez, Christian Pasquali, Rafael Simó

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11 Citations (Scopus)

Abstract

© 2017, Published with license by Taylor & Francis. © 2017 Cristina Solà-Adell, Patricia Bogdanov, Cristina Hernàndez, Joel Sampedro, Marta Valeri, Marta Garcia-Ramirez, Christian Pasquali, and Rafael Simó. 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 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. 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.
Original languageEnglish
Pages (from-to)1273-1286
JournalCurrent Eye Research
Volume42
Issue number9
DOIs
Publication statusPublished - 2 Sep 2017

Keywords

  • Calcium dobesilate
  • diabetic retinopathy
  • retinal neuroprotection
  • vascular leakage

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