Nutraceuticals for the Treatment of Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus and is characterized by degeneration of retinal neurons and neoangiogenesis, causing a severe threat to vision. Nowadays, the principal treatment options for DR are laser photocoagulation, vitreoretinal surgery, or intravitreal injection of drugs targeting vascular endothelial growth factor. However, these treatments only act at advanced stages of DR, have short term efficacy, and cause side effects. Treatment with nutraceuticals (foods providing medical or health benefits) at early stages of DR may represent a reasonable alternative to act upstream of the disease, preventing its progression. In particular, in vitro and in vivo studies have revealed that a variety of nutraceuticals have significant antioxidant and anti-inflammatory properties that may inhibit the early diabetes-driven molecular mechanisms that induce DR, reducing both the neural and vascular damage typical of DR. Although most studies are limited to animal models and there is the problem of low bioavailability for many nutraceuticals, the use of these compounds may represent a natural alternative method to standard DR treatments.

Keywords: carotenoids; flavonoids; inflammation; microvascular lesions; neoangiogenesis; oxidative stress; polyphenols; retina; saponins.

Figure 1

Summary of all the nutraceuticals cited in the present review. The compounds are listed according to their chemical classes, including polyphenols (both flavonoids and non-flavonoids), carotenoids, and saponins. Other compounds that do not belong to any of these classes or that are mixtures of different chemicals are classified as “other”. AKBA: Acetyl-11-keto-β-boswellic acid.

Figure 2

Schematic reconstruction of the events triggered in the retina by hyperglycemia and reinforced by oxidative stress in a vicious cycle. Formation of advanced glycation end-products (AGE) as well as the activation of protein kinase C (PKC), of the polyol pathway, and of the hexosamine pathway, are the main diabetes-induced abnormalities related to diabetic retinopathy.

Figure 3

Summary of the effects induced by nutraceuticals as described in the studies reviewed herein. Nutraceuticals exert positive effects in diabetic retinopathy, counteracting the diabetes-induced changes by decreasing (yellow arrows) or increasing (green arrows) the expression/activation of specific factors or the occurrence of some events. 8-OHdG: 8-hydroxy-2′-deoxyguanosine; AGE: Advanced glycation end-products; AKT: Protein kinase B; Bax: Bcl-2-associated X protein; Bcl-2: B cell lymphoma 2; BDNF: Brain-derived neurotrophic factor; BRB: Blood-retina barrier; CAT: Catalase; Erk 1/2: Extracellular signal-regulated kinase 1/2; GFAP: Glial fibrillary acidic protein; GSH: Glutathione; HIF-1α: Hypoxia inducible factor 1α; HO-1: Heme oxygenase-1; ICAM-1: Intercellular cell adhesion molecule 1; IL-1β: Interleukin 1 beta; MMP-9: Matrix metalloproteinase-9; NADPH: Nicotinamide adenine dinucleotide phosphate; Nf-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; O-GlcNAc: O-linked β-N-acetylglucosamine; NGF: Nerve growth factor; NO: Nitric oxide; Nrf2: Transcription nuclear factor erythroid-2-related factor-2; ROS: Reactive oxygen species; SOD: Superoxide dismutase; TNFα: tumor necrosis factor alpha; Trk-B: Tyrosine receptor kinase B; TUNEL: Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling; VEGF: Vascular endothelial growth factor; VEGFR2: Vascular endothelial growth factor receptor 2; ZO-1: Zonula occludens 1.

Figure 4

Hypothetic cascade of events induced by high glucose in the retina leading to diabetic retinopathy and the effects of nutraceuticals. See text for explanation.