Resveratrol: Its Path from Isolation to Therapeutic Action in Eye Diseases

Abstract

Due to the confirmed therapeutic potential of resveratrol (Rv) for eye diseases, namely its powerful anti-angiogenic and antioxidant effects, this molecule must be studied more deeply. Nowadays, the pharmaceutic and pharmacokinetic available studies offer a troubling picture because of its low stability and bioavailability. To overcome this problem, researchers started to design and create different delivery systems that could improve the delivery amount of Rv. Therefore, this review aims to shed light on the proper and efficient techniques to isolate, purify and quantify the Rv molecule, and how this therapeutic molecule can be a part of a delivery system. The Rv great impact on aspects regarding its stability, bioavailability and absorption are also debated here, based on the existent literature on in vitro and in vivo human and animal studies. Moreover, after its absorption the Rv influence at the molecular level in ocular pathologies is described. In addition, the present review summarizes the available literature about Rv, hoping that Rv will gain more attention to investigate its unexplored side.

Keywords: VEGF; delivery systems; ocular pathologies; resveratrol; sirtuins.

Figure 1

The chemical structure of the two conformations of resveratrol and its main monomeric derivatives.

Figure 2

The connection between the resveratrol biosynthesis pathway and the biochemical pathway for synthesis of flavonoids, represented by the first intermediate called chalcone. The enzymes involved in the chemical reactions have been abbreviated as follows: PAL—Phenylalanine ammonia lyase; C4H—Cinnamate-4-hydroxylase; TAL—Tyrosine ammonia-lyase; 4CL—Coumaroyl-CoA ligase; STS—Stilbene synthase; CHS—Chalcone synthase.

Figure 3

Overview of the biotransformation process of resveratrol in the human body. After oral administration, the parent molecule undergoes sulfation by SULT1A1 in the intestine and liver (RSV-SUL). Similarly, the enzymes UGT1A1 and UGTA9, expressed at intestinal and hepatic level, catalyze the formation of glucuronidated metabolites (RSV-GLU). Piceid, piceatannol, 3,4′-dihydroxy-trans-stilbene, dihydroresveratrol (DHR) and 3,4′-dihydroxybibenzyl (lunularin) (L) are obtained after the gut microbiome action on the ingested compound. Finally, the compounds are absorbed into the bloodstream and are subsequently eliminated from the body through urine or feces.

Figure 4

Pathophysiological pathways of diabetic retinopathy as a consequence of hyperglycemia. Abbreviations: AGEs—advance glycation end products; FADH2—redox cofactor flavin adenine dinucleotide; GLAST—glutamate transporter protein; NADH—reduced form of nicotinamide adenine dinucleotide; NMDA—N-methyl D-aspartate receptor; TNF—tumor necrosis factor; VEGF—vascular endothelium growth factor (adapted from [130]).

Figure 5

The interplay between key molecules implicated in the management of diabetic retinopathy. Abbreviations: AMPK—AMP-activated protein kinase, SIRT1—Sirtuin 1, NF-kB—Nuclear factor-kB, PGC-1α—Peroxisome proliferator-activated receptor-gamma coactivator, mTOR—Mammalian target of rapamycin, LKB1—liver kinase B1, AMP—Adenosine monophosphate, ATP—Adenosine 5′-triphosphate, NAD⁺—Nicotinamide adenine dinucleotide.

Figure 6

Structural aspects regarding the main resveratrol delivery systems successfully used to date.