Adjuvant Therapies in Diabetic Retinopathy as an Early Approach to Delay Its Progression: The Importance of Oxidative Stress and Inflammation

Ricardo Raúl Robles-Rivera, José Alberto Castellanos-González, Cecilia Olvera-Montaño, Raúl Alonso Flores-Martin, Ana Karen López-Contreras, Diana Esperanza Arevalo-Simental, Ernesto Germán Cardona-Muñoz, Luis Miguel Roman-Pintos, Adolfo Daniel Rodríguez-Carrizalez, Ricardo Raúl Robles-Rivera, José Alberto Castellanos-González, Cecilia Olvera-Montaño, Raúl Alonso Flores-Martin, Ana Karen López-Contreras, Diana Esperanza Arevalo-Simental, Ernesto Germán Cardona-Muñoz, Luis Miguel Roman-Pintos, Adolfo Daniel Rodríguez-Carrizalez

Abstract

Diabetes mellitus (DM) is a progressive disease induced by a sustained state of chronic hyperglycemia that can lead to several complications targeting highly metabolic cells. Diabetic retinopathy (DR) is a multifactorial microvascular complication of DM, with high prevalence, which can ultimately lead to visual impairment. The genesis of DR involves a complex variety of pathways such as oxidative stress, inflammation, apoptosis, neurodegeneration, angiogenesis, lipid peroxidation, and endoplasmic reticulum (ER) stress, each possessing potential therapeutic biomarkers. A specific treatment has yet to be developed for early stages of DR since no management is given other than glycemic control until the proliferative stage develops, offering a poor visual prognosis to the patient. In this narrative review article, we evaluate different dietary regimens, such as the Mediterranean diet, Dietary Pattern to Stop Hypertension (DASH) and their functional foods, and low-calorie diets (LCDs). Nutraceuticals have also been assessed in DR on account of their antioxidant, anti-inflammatory, and antiangiogenic properties, which may have an important impact on the physiopathology of DR. These nutraceuticals have shown to lower reactive oxygen species (ROS), important inflammatory factors, cytokines, and endothelial damage biomarkers either as monotherapies or combined therapies or concomitantly with established diabetes management or nonconventional adjuvant drugs like topical nonsteroidal anti-inflammatory drugs (NSAIDs).

Conflict of interest statement

All authors of this review article declare no conflict of interest.

Copyright © 2020 Ricardo Raúl Robles-Rivera et al.

Figures

Figure 1
Figure 1
Diabetic retinopathy physiopathology pyramid. This is a representation of DR's pathophysiology on how every step leads to the next upper one. Hyperglycemic state is the first step, followed by neurodegeneration and endothelial dysfunction, underlying oxidative stress, endoplasmic reticulum (ER) stress, lipid metabolism abnormalities, apoptosis, and autophagy as a complex interconnected pathophysiology leading to retinal damage in DR.
Figure 2
Figure 2
DR's physiopathology and biomarkers for each intervention. Hyperglycemia induces a variety of biochemical responses derived in angiogenesis (as shown by VEGF and endothelial damage), apoptosis, and retinal dysfunction; here, we describe where each intervention acts in these complex pathways by inhibiting the shown biomarker. Abbreviations: VEGF: vascular endothelial growth factor; G3P: glyceraldehyde 3-phosphate; DAG: diacylglycerol; AGEs: advanced glycation end products; RAGE: receptor for advanced glycation end products; PKC: protein kinase C; NOX: NADPH (nicotinamide adenine dinucleotide phosphate) oxidase; ROS: reactive oxygen species; SOD: superoxide dismutase; MnSOD: manganese superoxide dismutase; GPx: glutathione peroxidase; GR: glutathione reductase; ICAM-1: intercellular adhesion molecule-1; VCAM-1: vascular cell adhesion molecule-1; MCP-1: monocyte chemoattractant protein-1; TNF-α: tumor necrosis factor-alpha; IL-6: interleukin-6; IL-8: interleukin-8; IL-1β: interleukin-1β; PUFAs: polyunsaturated fatty acids; AIF-1: apoptosis-inducing factor-1; Bax: Bcl-2-associated X protein; LEAM: leukocyte-endothelium adhesion molecules; DASH: Dietary Pattern to Stop Hypertension.
Figure 3
Figure 3
A model of nontraditional therapies focused for diabetic retinopathy to diminish its progression from early to proliferative stages. Represents the two main topics focusing on diet and nutraceuticals either alone or combined, both as an alternative adjuvant therapy for DR. Abbreviations: DR: diabetic retinopathy; DASH: Dietary Approaches to Stop Hypertension; LCD: low-calorie diet; VLCD: very low-calorie diet; NSAIDs: nonsteroidal anti-inflammatory drugs.

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