Anti-inflammatory Effect of Curcumin, Homotaurine, Vitamin D3 on Human Vitreous in Patients With Diabetic Retinopathy

Diabetic retinopathy is one of the most common complications of diabetes mellitus and is a leading cause of vision loss and blindness in the working-age population worldwide. DR is being recognized as a neurodegenerative disease of the retina as opposed to previously considered solely as a microvascular disease. Progressive blindness is due to the long-term accumulation of pathological abnormalities in the retina of hyperglycemic patients. In the initial phase, non-proliferative diabetic retinopathy (NPDR) is almost asymptomatic with the onset of microhemorrhagic and microischemic episodes and an increase in vascular permeability. Subsequently, the progression of the disease is accompanied by the onset of a chronic inflammatory state and neovascularization in a vicious circle that feeds and determines the accumulation of damage to the retina through hypoxia, oxidative stress and widespread neurodegeneration. Among metabolites, hyperglycemia is known to be the major factor which activates several metabolic pathways harmful for retina. Moreover, an increased level of glutamate has been reported in the diabetic retina and also in the vitreous of diabetic patients, suggesting a neurotoxic role of glutamate which may damage retinal neurons and especially retinal ganglion cells by excitotoxicity. In proliferative diabetic retinopathy (PDR), vitreous humor undergoes structural and molecular changes, with changes also in composition, which play a central role in supporting disease progression.The vitreous, 4 ml in volume, is a transparent gel-like structure which fills the space between the lens and the retina. It is composed of 98-99% of water with traces of cations, ions, proteins (mainly collagen) and polysaccharides such as hyaluronic acid. In PDR patients undergoing pars plana vitrectomy, vitreous samples are characterized by altered levels of bioactive molecules with pro-angiogenic, proinflammatory and neuromodulatory activities. So, it is clear that the vitreous acts as a reservoir of soluble signaling mediators that could exacerbate retinal damage. On the other hand, the vitreous obtained from patients with PDR can be a powerful tool to evaluate the anti-angiogenic / anti-inflammatory activity of new biomolecules that could be potential candidates for the treatment of diabetic vitreoretinopathy. Currently, PDR is treated with laser photocoagulation, vitreoretinal surgery or intravitreal injection of drugs targeted to the vascular endothelial growth factor (VEGF) and steroid agents.However, these protocols are effective in the short term, cause side effects and, above all, are indicated only for advanced stages of the disease. So, noninvasive, nondestructive, and longer-duration treatment options are also needed. Recently, research efforts have been made to identify neuroprotective drugs able to prevent visual field loss and preserve visual function and a promising alternative for the treatment of early-stage NPDR comes from nutraceuticals. In fact, in vitro and in vivo studies have revealed that a variety of nutraceuticals has important antioxidant and anti-inflammatory properties that can compromise the first diabetes-driven molecular events that cause vitreoretinopathy, acting upstream of the disease. Based on the results of several investigations, it is reasonable to assert that a single constituent that affects one target has limited efficacy in preventing the progression of multifactorial diseases. A large body of research revealed that the use of a combination of compounds with synergistic multitarget effects may offer a more powerful approach for disease prevention, including retinal neurodegeneration. In experimental models of retinal neurodegeneration it has been shown that cotreatment of citicoline and homotaurine has a direct neuroprotective effect on primary retinal cells exposed to glutamate toxicity and HG levels. Glutamate-induced excitotoxicity is implicated in the pathophysiology of several degenerative diseases of the retina, including glaucoma. Moreover, HG-induced neurotoxicity is a characteristic of diabetic retinopathy. Curcumin, a yellowish non-flavonoid polyphenol that constitutes the main active compound of Curcuma longa, is widely known for its antioxidant and anti-inflammatory properties . Many studies have also described its marked protective effect on retinal cells against oxidative stress and inflammation. Lastly, vitamin D levels appeared to be lower in diabetes mellitus type 2 patients and this could have therapeutic implications. Therefore, the aim of the investigator's study is to analyze the soluble mediators of inflammation and angiogenesis in the vitreous of patients with diabetic retinopathy treated with homotaurine, curcumin and vitamin D3.