Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes
Cristina Solà-Adell1,2, Patricia Bogdanov1,2, Cristina Hernández1,2
1a Diabetes and Metabolism Research Unit , Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona , Barcelona , Spain.
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.
Insights
Calcium dobesilate monohydrate (CaD) shows neuroprotective effects in diabetic retinopathy (DR) by reducing neurodegeneration and vascular leakage. This study reveals CaD
Area of Science:
- Ophthalmology
- Diabetology
- Pharmacology
Background:
- Diabetic retinopathy (DR) is a leading cause of vision loss, characterized by neurodegeneration and vascular complications.
- The precise mechanisms underlying the therapeutic effects of Calcium dobesilate monohydrate (CaD) in DR are not fully understood.
- Early intervention targeting neuroprotection and vascular integrity is crucial for managing DR.
Purpose of the Study:
- To investigate the neuroprotective potential of CaD in an experimental model of DR.
- To determine if CaD prevents early DR pathogenesis, including neurodegeneration and vascular leakage.
- To examine the role of specific mediators such as glutamate, endothelin-1 (ET-1), oxidative stress, and VEGF in CaD's effects.
Main Methods:
- Diabetic (db/db) mice and non-diabetic controls were treated with CaD or vehicle.
- Functional retinal activity was assessed using electroretinography.
- Neurodegeneration and microvascular changes were evaluated through immunohistochemistry, Western blot, and glutamate level determination via HPLC.
Main Results:
- CaD treatment significantly reduced glial activation and apoptosis, improving electroretinogram parameters.
- CaD prevented the diabetes-induced upregulation of ET-1 and its receptors (ETA-R, ETB-R).
- CaD downregulated glutamate transporter GLAST, reduced glutamate levels, and mitigated oxidative stress, VEGF, and PKC delta-p38 MAPK pathway activation, decreasing vascular leakage.
Conclusions:
- CaD demonstrates significant neuroprotection in an experimental DR model.
- CaD effectively prevents the overexpression of ET-1 and its receptors in the diabetic retina.
- These findings support CaD's potential as a therapeutic agent for early-stage DR, warranting clinical trials.
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