Mechanisms of retinal neuroprotection of calcium dobesilate: therapeutic implications

Current treatments for diabetic retinopathy (DR) are based on laser photocoagulation and intravitreal injections of corticosteroids or anti-vascular endothelial growth factor (VEGF) agents. These treatments are applicable only at advanced stages of the disease. In addition, they are expensive, require a vitreoretinal specialist and are associated with significant adverse effects. Therefore, new pharmacological treatments for the early stages of the disease are needed. Although DR is still often considered a microcirculatory disease of the retina, growing evidence suggests that retinal neurodegeneration is an early event in the pathogenesis of DR which participates in the microcirculatory abnormalities. For this reason, therapeutic strategies based on neuroprotection should be effective not only in preventing or arresting retinal neurodegeneration, but also in preventing the development and progression of the microvascular abnormalities that exist in the early stages of DR (Simó and Hernández, 2015). However, when the early stages of DR are the therapeutic target, it would be inconceivable to recommend an aggressive treatment such as intravitreal injections. Therefore, systemic treatments addressed to block the main pathways involved in the pathogenesis of DR are needed. However, most of these treatments can barely reach the retina at pharmacological concentrations and, in addition, could have serious adverse effects. Nevertheless, three classes of oral drugs have emerged as potential systemic treatments for DR: renin-angiotensin (RAS) system blockers, fenofibrate, and calcium dobesilate monohydrate (CaD). Regarding RAS, the current clinical evidence does not support the concept that they possess an extra value in preventing or arresting the progression of DR in hypertensive patients when compared with other anti-hypertensive agents. In the case of fenofibrate, several sub-studies have demonstrated its usefulness in arresting the progression of DR but not in preventing its development. Therefore, it seems reasonable to propose its use for patients with preexisting DR. However, fenofibrate for DR treatment has been approved only in Australia, Singapore, Philippines and Malaysia. By contrast CaD has been approved for the treatment of DR in numerous countries and clinical evidence supports its use in early stages of DR. Although CaD has been approved for the treatment of DR for many years, it has not been widely used in clinical practice. A poor understanding of its mechanisms of action has been one of the reasons for this. However, recent experimental evidence showing the neuroprotective action of CaD makes it a very attractive drug for early stages of DR. In fact, the American Diabetes Association in its more recent position statement defines DR as a “highly specific neurovascular complication” (Solomon et al., 2017). Therefore, drugs such as CaD which exert a multifaceted acction on neurovascular unit impairment can be contemplated as excellent candidates for targeting the early stages of DR. Systemic actions of CaD: The antioxidant and anti-inflammatory properties of CaD are among the systemic actions of CaD that could exert beneficial effects in DR. In addition, the beneficial hemorrheologic effects based on the evidence of CaD in reducing blood hyperviscosity and platelet aggregation facilitate capillary perfusion and reduce the inflammatory status.