The increased level of glutamate in diabetes is associated with glutamate excitotoxicity which increases calcium influx and initiates proapoptotic signaling cascades.37,38 Such events are likely to be involved in the apoptosis of neurons within the retina in diabetes.76C78 Deficiency of neuroprotective factors The neuronal compartment possesses certain neuroprotective local factors including pigment epithelium-derived factor (PEDF),79C82 brain-derived neurotrophic factor (BDNF),83,84 and nerve growth factor (NGF).85,86 It is postulated that they protect against oxidative stress and glutamate excitotoxicity, thereby having a critical role in the prevention of neuronal damage associated with DR. effective way to manage diabetic retinopathy is usually by primary prevention such as hyperglycemia control. While the current mainstay for the management of severe and proliferative diabetic retinopathy is usually laser photocoagulation, its role is usually diminishing with the development of newer drugs including corticosteroids, antioxidants, and antiangiogenic and anti-VEGF brokers which work as an adjunct to laser therapy or independently. The current pharmacotherapy of diabetic retinopathy is usually incomplete as a single treatment option in view of limited efficacy and short-term effect. There Azelastine HCl (Allergodil) is a definite clinical need to develop new pharmacological therapies for diabetic retinopathy, particularly ones which would Azelastine HCl (Allergodil) be effective through the oral route and help recover lost vision. The increasing understanding of the mechanisms of diabetic retinopathy and its biomarkers is likely to help generate better and more effective medications. strong class=”kwd-title” Keywords: mechanism, pharmacotherapy microvascular changes, neurodegeneration, laser, progression Introduction Diabetic retinopathy (DR) is usually a highly specific neuroretinal and microvascular complication of diabetes caused by various abnormal metabolic pathways brought on by uncontrolled hyperglycemia. In the beginning, the disease is usually asymptomatic, but prolonged poor control of diabetes prospects to permanent pathological changes in the retina resulting in blurred vision, floaters, distortion, and total loss of vision.1C6 These pathological changes include microaneurysms, hemorrhages and exudates (nonproliferative DR [NPDR]), formation of new abnormal blood vessels or retinal neovascularization (proliferative DR [PDR]), and diabetic macular edema (DME). DR is usually emerging as one of the leading causes of blindness in both developing and developed countries. It is estimated that nearly 400 million people are affected with diabetes worldwide and the number is likely to reach close to 600 million by 2035.7,8 Over 90 million people are estimated to be suffering from DR, of which 17 million have PDR, 21 million have DME, and 28 million have severe vision-threatening DR.9,10 A thorough and enhanced understanding of the various pathways and clinical biomarkers involved in the pathogenesis of DR is a prerequisite to developing therapeutic strategies. At the molecular level, the etiology of Azelastine HCl (Allergodil) DR is usually highly complex, with numerous interlinked mechanisms causing adaptive, functional, and structural changes in both the microvasculature and neuroglia. These in turn lead to cellular damage in the retina which is usually often permanent. However, despite extensive research, the understanding of these TLN2 pathways remains limited and the initiator of the DR cascade is usually unclear.3,5,9 It is currently understood that prolonged hyperglycemia causes increased polyol pathway flux,11,12 increased advanced glycation end-product (AGE) formation,13,14 abnormal activation of signaling cascades such as activation of protein kinase C (PKC) pathway,15C17 increased hexosamine pathway flux,10,18C22 and peripheral nerve damage.23 All these changes lead Azelastine HCl (Allergodil) to increased oxidative stress19, 24C27 and inflammatory assault28C31 to the retina resulting in adaptive structural and functional changes.9,32,33 Progression of DR is characterized by loss of pericytes, basement membrane thickening, formation of microaneurysms, neovascularization, and bloodCretinal barrier breakdown.9 The disease progresses through increased vascular permeability and retinal ischemia resulting in retinal neovascularization and retinal thickening.34 Conventionally, the clinical classification, etiology, and management strategy of DR were solely based on microvascular changes in the retina. The role of neuroretinal alterations in Azelastine HCl (Allergodil) the etiology of DR were not recognized until the 1960s, when Wolter35 and Bloodworth36 documented the pathological degeneration of neurons in the retina of diabetic patients. Although the exact relation between neuroretinal changes and DR is still unclear, research over the past decade has enhanced our understanding about numerous neuroretinal pathways and clinical biomarkers involved in the pathogenesis of DR. The role of neuroretinal alterations and neuroretinal inflammation in the formation and progression of DR is usually apparent, and therapies targeting the prevention of neuroretinal damage from diabetes are also underway in different stages of clinical and preclinical trials.37,38 Biomarkers and mechanisms for microvascular dysfunction Glycemic level Evidence of hyperglycemia and its duration as a major risk factor in the progression of DR is plentiful.10,39 In diabetes, due to prolonged exposure to high blood glucose concentration, endothelial cells lining the microvasculature experience oxidative stress and cause increased adhesive interactions between circulating inflammatory cells and additionally activate them. This prospects to increased synthesis of inflammatory mediators by blood and endothelial cells promoted by cytokines.26 Lipid level Dyslipidemia is found to increase the risk of DR, especially DME.40C42 The exact role of an increased lipid level in.