Resumen de Effects of neurodegeneration on microvascular abnormalities in diabetic retinopathy. Study of pathogenic mechanisms and therapeutic implications: the exemple of calcium dobesilate
Diabetic retinopathy (DR) is the most common complication of diabetes and one of the leading causes of blindness among working-age people in developed countries. Although DR has traditionally been considered a microcirculatory disease of the retina, it is currently defined as a specific neurovascular complication of diabetes. In addition, growing evidence suggests that retinal neurodegeneration is an early event in the pathogenesis of the DR, which in turn can participate in the microcirculatory abnormalities. Despite the progression made in DR knowledge, the current treatments are mainly directed against the advanced stages of the disease. Therefore, new therapies aimed at preventing or arresting neurodegeneration and microvascular abnormalities that appear in the early stages of DR will cover an important scientific gap in the treatment of DR. Given that RD is a multifactorial pathology; therapeutic strategies based on inhibiting different pathogenic pathways could be able to protect the entire neurovascular unit of the retina. In this thesis, we have studied the mechanisms by which retinal neurodegeneration participate in the early microvascular alterations of the RD through the example of calcium dobesilate (CaD).
CaD is a chemical compound developed in the early 70's and it is approved in different countries for the treatment of DR. Among the main actions of the CaD there is an anti-oxidant and anti-inflammatory action, as well as a vasoprotective action. Nevertheless, the clinical trials regarding its effectiveness in advanced stages of DR remains controversial and, therefore, CaD is not widely used in clinical practice. This thesis has shown for the first time that CaD administration has a dual effect protecting both the neuroretina and its vasculature. We have found significant reductions of glial reactivity and neuronal death, two of the main biomarkers of retinal neurodegeneration. In addition, an improvement in the vascular function has been detected while preserving the integrity of the hematoretinal barrier. These findings run in parallel with a significant improvement of neurodysfunction. Thus, the electroretinographic recordings have shown a significant improvement after the treatment with CaD.
Regarding the mechanisms of action of CaD, an improvement in the metabolism of the glutamate as a result of an enhancement of GLAST transporter has been detected. This transporter plays an important role in the synaptic clearance of glutamate. According to these results, a reduction in retinal levels of glutamate has also been observed. Another mechanism of action of CaD is the decrease in ET-1 and its A and B receptors (ETA-R, ETB-R), which are involved in microvascular and neurodegenerative damage, respectively. On the other hand, our work has revealed that the CaD has an effect on the PKC-delta / p38-MAPK pathway. This pathway is activated in diabetes mainly due to oxidative stress and pro-inflammatory cytokines characteristic of the diabetic milieu. The decrease in the expression of both kinases is involved in the improvement in the sealing function of blood-retinal barrier. Furthermore, PKC-delta / p38-MAPK pathway is also involved in the activation of NF-B and the synthesis of pro-inflammatory proteins. CaD treatment avoids the translocation of NF-B, thus preventing the inactivation of IKKb-and decreases the expression of pro-inflammatory cytokines and chemokines such as TNF-α, IL-6, IL-8, and MCP-1. Finally, we have found that CaD has anti-oxidant activity that affects both the formation of free radicals of oxygen and nitrogen.
In summary, our results suggest that drugs such as CaD with capacity to protect the neurovascular unit could be useful for the treatment of early stages of DR.
