Diabetic retinopathy (DR) is a complication of diabetes that affects the eyes, causing severe visual impairment. It is induced by damage to the blood vessels in the light-sensitive part of the eye, the retina, with the vasculopathy being the main involved pathophysiologic mechanism
[24]. It can develop in subjects affected by both type 1 and type 2 diabetes. There are two types of retinopathies. The first is the early diabetic retinopathy, also known as nonproliferative diabetic retinopathy (NPDR). As the disease progresses, the walls of the blood vessels weaken and are subject to microaneurysms, small swellings that, when damaged, lead to bleeding. Then there is the risk of an accumulation of fluids, i.e., formation of edema, in the macula, which cause reduced vision. The second type is proliferative or advanced diabetic retinopathy (PDR). It is the most serious type because it coincides with the abnormal growth of new blood vessels damaging the retina. Diabetes is, in fact, associated with a growth of weak blood vessels, more prone to rupture, or smaller vessels, and this leads to a lower oxygen transport capacity to the retinal tissues. As a result, new vessels are stimulated by the formation of ischemic areas in the retina. In fact, retinal microvascular disease is an early compromission, induced by low-grade, persistent leukocyte activation, which causes repeated episodes of capillary occlusion and progressive retinal ischemia
[25]. This situation can induce detachment of the retina or an abnormal flow of fluid into the eye, causing glaucoma. The underlying molecular mechanisms associated with vascular dysfunction, especially endothelial dysfunction, in DR are multifactorial. Chronic inflammation, oxidative stress, leukostasis, dysregulated growth factors and cytokines, and disruption of peroxisome proliferator-activated receptor-γ are mainly involved
[26]. Diabetic retinopathy is prevalent in around 35% of patients with diabetes. The disease progresses slowly, causing damages that become progressively irreversible. Unfortunately, treatment options are limited. As therapeutic approaches, photocoagulation of the ischemic areas of the retina to stabilized blood vessels, intravitreal injections with VEGF-inhibitory agents or corticosteroids, and ocular surgery can be applied
[27]. It is worth noting that anti-VEGF agents used in clinical practice, such as ranibizumab, bevacizumab, and aflibercept, are considerably different in terms of molecular interactions when they bind with VEGF
[28]; therefore, characterization of such features can improve the design of novel biological drugs potentially useful in clinical practice. Recent findings hypothesize that retinal neurodegeneration represents a critical, early component of DR. It occurs prior to the vascular changes classically associated with DR and contributes to disease pathogenesis
[29][30]. In the retina, neurons, glia, and vasculature form the blood–retinal barrier (BRB), which functions as the maintenance of energy, homeostasis, and neurotransmitter regulation. In the progression of diabetes, the BRB is damaged early and its breakdown is sustained by RPE secretion of different factors, among which the main ones are vascular endothelial growth factor (VEGF) and proinflammatory cytokines (i.e., TNF-α, IL-6, IL-1β)
[31]. It is interesting to note that VEGF may act as a negative regulator of pericyte function, with these cells being involved in early BRB abnormalities in diabetic retinopathy
[32]. During progression of DR, the retina is infiltrated by the above mentioned secreted factors’ cells and serum proteins, further damaging blood vessels and neurons. Moreover, in addition to vascular damage and the loss of BRB integrity, other neurodegenerative changes occur in the retina such as apoptosis, glial cell reactivity, microglial activation, and altered glutamate metabolism that could prove some of the functional deficits in vision
[29][33]. Additionally, to point out the neurodegeneration, clinical evidence indicates CNS lesions in patients with diabetic retinopathy; detection of small punctate white matter lesions in the brain and cortical atrophy in some regions suggests that there is an association between retinopathy and brain tissue damage
[34]. Other studies highlight that diabetes-induced retinal neurodegeneration and brain neurodegenerative diseases share common pathogenic pathways. Indeed, DR patients might exhibit abnormalities in the central nervous system, often showing impaired cognition and increased risks of dementia as well as Alzheimer disease
[35].