# Diabetic Retinopathy and Ocular Melanoma: How Far We Are?
## 3 Diabetic Retinopathy, Angiogenesis and Anti-Angiogenic Therapy  
Diabetes is a chronic disease related to genetic predisposition and risk factors, i.e., obesity, aging, physical inactivity; particularly, diabetes mellitus is a chronic and progressive disease influencing a considerable percentage of the population worldwide [25; 41; 42; 43; 44; 45]. Several works have been published on natural nutraceuticals [46; 47; 48; 49; 50; 51] as well as new formulations [25; 41; 42] used for managing diabetes [52; 53; 54]. Diabetic retinopathy is known to lead to blindness, progressively damaging retinal microvasculature. This disease has two specifications, proliferative diabetic retinopathy (PDR) and non-proliferative diabetic retinopathy (NPDR). The first comprises retinal neovascularization under low oxygen, and the second causes changes in internal retinal microvasculature, which may be mild, moderate or severe, and is also related to diabetic macular edema (DME) [55; 56; 57; 58]. The new blood vessels are delicate and, without proper treatment, lead to blindness. In DR there is also a high vascular permeability that can cause fluid accumulation and macula's retinal haemorrhages [59]. DR has long been seen as a microvascular problem, but now it has also been recognized that retinal microvasculature is governed by neurons and glia. These are the first cells to undergo changes, occurring before the clinical manifestation of vascular lesions. Advances have been made to treat vascular changes, but there is no therapy yet for early neuro-glial disorders in DR [5]. Many pre-clinical and clinical studies focus on vascular dysfunction in the DR, including damaged endothelial cells, pericyte death, retinal capillary basement membrane thickness and modification of tight joints. Nevertheless, diabetic microvasculopathy does not clarify the vulnerability of peripheral nerves, brain complexities and retinal impairment. The concept of the neurodegenerative aspect of RD began to emerge in the late 1990s. There are several reviews available in the literature reporting that in this disease there is vulnerability and premature death of neurons, but none of them clarify the pathophysiological mechanisms responsible for neurodegeneration [60; 61]. The most affected cells--retinal ganglion cells (RGCs)--have an elevated rate of apoptosis, especially in the outer nuclear layer, with a decrease in photoreceptors in the first six months of diabetes [62; 63; 64; 65]. Molecular analyses were also performed where it was shown that proteins relevant to photoreceptor function (e.g., rhodopsin) undergo changes prior to the onset of microangiopathy in diabetes, which is consistent with this observation [66]. Activation and dysfunction of glial cells is yet another individuality of diabetic-induced retinal neurodegeneration and has been widely studied. The relevant retinal glial cells--Muller glial cells (MGCs)--play a crucial role in retinal metabolism and are therefore vulnerable to any alteration in this metabolism. Positive regulation of glial fibrillary acidic protein (GFAP) by MGCs is indicative of retinal metabolic stress, and this occurs in animal models as well as in the tissues of diabetic patients with no to mild NPDR [67; 68]. As a result, microglia cells are activated and proinflammatory mediators are produced, stimulating neuro-glial and vascular dysfunction [69]. These imbalances in neurons and glial cells also cause functional changes that occur prior to vascular lesions clinically found in RD. Thus, diabetes is known to directly affect neuroretina and is not a consequence of the breakdown of the retinal blood barrier. In diabetes, biochemical pathways related to neurodegeneration and vascular dysfunction are activated, with more angiogenic and inflammatory mediators being expressed and aberrant growth factor activated.