NON-PROLIFERATIVE DIABETIC RETINOPATHY Normal retinal blood vessels are watertight and do not leak

NON-PROLIFERATIVE DIABETIC RETINOPATHY
Normal retinal blood vessels are watertight and do not leak. Non-proliferative diabetic retinopathy is the early stage of the disease, in which symptoms will be microaneurysms (small bulges in blood vessels of the retina that often leak fluid), retinal hemorrhages (tiny spots of blood that leak into the retina), hard exudates (deposits of cholesterol or other fats from the blood that have leaked into the retina), and cotton wool spots. Swelling, thickening and fluid leaking from the retina’s blood vessels caused the macula region. When it is swollen, the macula doesn’t function properly. With increasing severity, retinal venous beading and intra-retinal microvascular abnormalities may leak fluid into the retina. These changes usually precede frank new vessel formation and the onset of PDR (Antonetti D.A et al,. 2013).

Figure 3. Clinical Signs of Normal (A, B), Proliferative diabetic retinopathy (C, D) and Age related macular degeneration (E, F). (Fundus and OCT image of patients. Narayana Nethralaya Super specialty Eye Hospital, Bangalore,India).

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PROLIFERATIVE DIABETIC RETINOPATHY
Micro-vascular pathology with capillary closure in the retina leads to hypoxia of tissue. The hypoxia leads to release of vasoproliferative factors which stimulate new blood vessel formation to provide better oxygenation of retinal tissue. These new vessels on the optic disc are called neovascularization of the disc (NVD) and those growing on the retina are called neovascularization elsewhere (NVE). These new vessels can bleed and produce haemorrhage into the vitreous. Recurrent vitreous haemorrhages and vitreous contraction can lead to tractional retinal detachments.
The natural course of PDR, emphasizes four fundamental processes: (1) the cycle of proliferation and regression typical of new vessels; (2) proliferation of fibrous tissue accompanying new vessels; (3) formation of adhesions between the fibro-vascular proliferations and the posterior vitreous surface; and (4) contraction of the posterior vitreous surface and associated proliferations (Figure 3 C and D).

1.4.3 DIABETIC MACULAR EDEMA
Diabetic Macular Edema (DME) is more prevalent characteristic of the proliferative from and has a serious risk to vision (Ali, F.A. 1997). DME has incidence rates of 11% to 14% in type I and type II diabetes (Romero Aroca, P, et al,. 2011). DME clinically correlate most closely with retinal central region and retinal blood vessels leakage. The macular region within the central retinal characterized by extremely high cone density and lateral vascularization relocation in inner retinal bipolar and ganglion cells, blocked the minimally photoreceptors light. Reduced the visual acuity and macular optical properties of subsequent thickening, by accumulation of fluid of blood borne materials of DME (Patelli, F. et al 2005). However changes in retinal structure is not the only cause of visual loss in DME, additionally the ion environment for neuronal transmission, inflammation, neurotransmitter and excitotoxicity these are potential mechanisms of retinal function loss. However, DME still remains with the clinical correlation of visual loss in both PDR and Non-proliferative diabetic retinopathy (Sander, B, et al,. 2007, Gardner, T.W et al,. 2009, and Lee, R et al,. 2015).
Activation of biochemical pathways guide to amplified oxidative stress, inflammation, induced leukostasis, induce growth factors, cytokines and vascular dysfunctions (Murugeswari P, et al,. 2008). Exposure to the high glucose causes structural modifications in retinal pigment epithelium, the range of growth factors and cytokines are secreted on behalf of barrier dysfunction (R. Simo et al,. 2010, T. Murakami et al,. 2013). RPE secretome plays a very important role in disease manifestation of DR, most of the studies have focused in understanding vascular leakage of endothelial cells (N. Arimura et al,. 2009). Anti-VEGF agents are preferred drug of choice for intra-vitreal injections of an effective suppression of neo-vascular proliferation in the retina.
However anti-VEGF agents have been used at random for DR, though ~ in 40% of the clinical symptoms of group of DR patients remain non-responders (P.Mitchell et al,.2011). Further, a few clinical studies have shown a fluorescent leakage distribution from the RPE layer, though an apparent evidence for DME was not observed (P. Murugeswari et al,. 2014 & M.A. Singer et al,. 2016). The above facts, implicates for involvement of additional factors beyond VEGF in DR disease progression. The RPE released cytokines and growth factors possibly break down the BRB (A.W. Stitt et al, 2015). In addition, the RPE barrier leakage and fluid accumulation is interconnected with the endothelial barrier in DR, and it could be considered widely as an additive insults. The complication of PDR and DME disease, its progression and management warrants a detailed study of the RPE secretory factors (Murugeswari P, et al, 2017).

THERAPEUTIC MANAGEMENTS OF DME
Concerning the treatment, laser retinal photocoagulation, vitreoctomy and anti-VEGF therapy, has been the standard care for PDR patients. The Diabetes Control and Complications Trial (DCCT) reported that74% decreased the risk of insulin dependent DM receiving concentrated treatment expected at tight glycemic control of developing DR. however type I diabetes reduced the risk of intensive therapy group after 15-18 years in original study (Lachin J.M, et al,. 2015). Another regulating risk factor to manipulate the development and progression of DR by hypertension, and a 2015 review shown blood pressure risk factor, overall intensive blood pressure controls the developing DR (Do, D.V, et al,. 2015). Fenofibrate is a medication, by prearranged to increase high density lipoprotein and reduce low density lipoprotein levels. It has antioxidant, anti-inflammatory, anti-angiogenic and anti-apoptotic properties. Report show that small group of fenofibrate treated patients received photocoagulation compared with no fenofibrate treatment (Noonan, J.E, et al,. 2013). Fenofibrate is not commonly used for the treatment of DR.
Pan retinal photocoagulation (PRP) involves encouraging weakening of abnormal neovascular tissue as the photocoagulation treatment of peripheral retina. The DR study evaluates the effects of PRP from small group of severe NPDR or PDR. The 5 years study report show of 50- 57% reduction in the PRP treated eyes in both NPDR and PDR group, non-treatment occurrence of severe visual loss (DRSG, 1987). Corticosteriods are also used for the treatment of DME by intravitreal injection in the eye. There are three synthetic corticosteroids that had been evaluate such as Triamcinolone asetonide, dexamethasone, and fluocinolone. All these injections of corticosteroids has beeen linked with risk of retinal tear, retinal detachment, vitreous hemorrhage, cataract, elevated intra ocular pressure and endophthalmitis (Sampat K.M. 2010 &Tolentino M, 2011). Fibrovascular proliferation induces vitreous haemorrhages and tractional retinal detachment in Macular region, necessitating surgical procedures such as vitrectomy. Endo-laser photocoagulation or pealing of epi-retinal membranes or vitreous replacement with silicone oil are the most common complications. In 1990s, were first reported the high levels of VEGF in DR treatment has been study used four anti-VEGF agents, such as Bevacizumab, Ranibizumab, Aflibercept and pegaptanib (Adamis, A.P et al,. 1994 and Aiello L. P, et al,. 1994).

COMPLICATIONS OF BEVACIZUMAB ANTIBODY
Currently widely used for treating patients with proliferative vitreo-retinopathy, proliferative diabetic retinopathy, retinal vein occlusion, diabetic macular edema and age related macular degeneration are anti-VEGF drugs. RPE is one of the crucial targets of Anti-VEGF treatments as abnormality of RPE with respect to its physiological functions and cellular properties almost always has a pathological outcome. Animal and clinical studies have revealed the most common complications of Anti-VEGF treatment are vitreous hemorrhage, tractional retinal detachment, fibrotic membrane formation and retinal pigment epithelial tears (Wong LJ, et al., 2008, Kubota T, et al., 2010). Clinical trials like ANCHOR, MARINA and CATT study have reported that 8-10% of patients on treatment with anti-VEGF agents develop dry AMD like phenotype with geographic atrophy. The above factors necessitate the need for alternatives as well as combinatorial therapy without compromising treatment efficacy. This caused financial burden on the patients as well as became a societal responsibility. In a pursuit to search for alternatives treatment option, we looked at resveratrol.
Resveratrol is an isolate from many fruits and other plant products, but grape skin and seeds appear to be the rich source of resveratrol. The advantage of RES is primarily its non-toxic property. It is US Food and Drug Administration approved as a dietary supplement and already part of clinical trials. Much research work in in-vitro and in-vivo models has been done for various diseases, such as diabetes, cancer, cardiology, etc. Animal models and in vitro culture systems are widely used in ophthalmology both for clinical as well as experimental studies, but there is limited work in understanding the role of RES in these models as a mode of therapy/rescue. It also maintains phagocytosis properties in cultured RPE cells in adverse treatment conditions. It has been shown to restore the normal function in dry AMD in animal and cell culture studies, but very less clinical, animal models and in-vitro study in ocular (eye) diseases. However, the mechanism of the antioxidant, anti-angiogenesis, anti- proliferation etc., and role has not yet been fully understood.
So the present study was carried out to study the resveratrol usefulness of the adverse effect of BEV on human retinal pigment epithelial cells.