LIPOIC ACID: ITS ANTIOXIDANT AND ANTI-INFLAMMATORY ROLE AND CLINICAL APPLICATIONS
Fabiana Andréa Moura1,2, Kívia Queiroz de Andrade1, Juliana Célia Farias dos Santos1,3 and Marília Oliveira Fonseca Goulart3,* ¹Faculdade de Nutrição/Universidade Fe deral de Alagoas (FANUT/UFAL), et al Current Topics in Medicinal Chemistry, 2015, 15, 000-000
Abstract: Lipoic acid (LA) is an antioxidant able to produce its effects in aqueous or lipophilic environments. Lipoate is the conjugate base of lipoic acid, and the most prevalent form of LA under physiological conditions. It presents a highly negative reduction potential, increases the expression of antioxidant enzymes and participates in the recycling of vitamins C and E. Due to these properties, LA is called the “universal antioxidant”. LA is also involved with anti-inflammatory action, independently of its antioxidant activity. This review was carried out, aiming to identify, analyze, and rationalize the various clinical, physiopathological and/or physiological situations in which LA, through oral supplementation, was tested on human and animal (rats and mice) models. LA was mainly tested in cardiovascular diseases (CVD), obesity, pain, inflammatory diseases and aging. LA uses in CVD and obesity, in humans, are controversial. On the other hand, beneficial effects on inflammation and pain were observed. LA supplementation in animal models may prolong life, has neuroprotective effects and presents positive effects against cancer. Differences observed in human and animal models can be due, in part, to different treatments (LA combined with other antioxidants, different doses) and to the variety of biomarkers investigated in animal experiments. These results suggest the need for further clinical trials to guide health professionals regarding the safety of prescription of this supplement.
- INTRODUCTION
Several studies aim to understand the physiopathological mechanisms of diseases, trying to identify potential agents, natural or synthetic, which effectively act in the prevention and/or treatment of them.
Among these substances, the 1,2-dithiolane-3-pentanoic acid, also known as α-lipoic acid (LA), lipoic acid or thioctic acid, has a redox active disulfide group. The carbon atom at C6 is chiral and the molecule exists as two enantiomers (R)-(+)-lipoic acid (RLA, the biologically active enantiomer) and (S)-(-)-lipoic acid (SLA) and as a racemic mixture (R/S)-lipoic acid (R/S-LA). The reduced form of LA, known as dihydrolipoic acid (DHLA), a dithiol compound, interacts with reactive oxygen and reactive nitrogen species (RONS) [1], and both forms act as antioxidants [2,3]. It is important to note that exogenous LA is rapidly internalized by cells and reduced to DHLA [4].
Due to its antioxidant and anti-inflammatory characteristics both in vitro and in vivo, oral supplementation of LA has been tested in diabetes treatment and its cardiometabolic complications [5], cancer [6], neurological disorders such as epilepsy [7], and others.
LA is able to produce its effects in aqueous or lipophilic [1,2,8] environments. Despite its insolubility in water (2.24 x 10-1 g/L), its conjugate base, lipoate, is more soluble and the most prevalent form of LA under physiological conditions. It has a highly negative redox potential of -0.32 V (vs. Normal Hydrogen Electrode) [9] and for all these reasons, the redox couple LA/DHLA is called an “universal antioxidant” [10,11]. In addition, LA is capable of reducing the oxidized form of nicotinamide adenine dinucleotide phosphate (NADP+), to restore the reduced/oxidized glutathione (GSH/GSSG) ratio, in favor of GSH, to increase the expression of antioxidant enzymes such as glutathione reductase [12], as well as to participate in the recycling of vitamins C and E [4] (Fig. 1).
Inflammation, a clinical condition closely related to redox imbalance, found in several diseases such as cardiovascular diseases (CVD) [13-16], cancer [17-19], and others [20-24], also presents its clinical evolution reduced/suppressed in the presence of LA. Among the proposed mechanisms to justify this action, there is suppression of genes involved in inflammatory activity such as Nuclear Factor Kappa-light-chain enhancer of Activated B Cells (NF-κB) [25-28], increase of the expression of genes for anti-inflammatory proteins, such as Nuclear erythroid 2-related factor (Nrf2) [29], as well as reduction in the concentration of several pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and Interleukin 6 (IL-6) [30,31], independent on its antioxidant activity [32] (Fig. 2). However, due to its accumulation in tissues after oral ingestion, as well as its pro-oxidant activity [9,33,34] the efficacy of oral supplementation of LA has been questioned [35,36].
Several reviews about LA have been published in several databases, in an attempt to elucidate its biochemical [37,38], clinical [4,39,40], pharmacological and/or nutritional [2,41,42] and antioxidant [1], [43-44] actions. An extensive survey, in the context of the use of LA in various pathologies was published by Shay in 2009, where the authors discuss the use of LA in diabetic polyneuropathy, in the vascular system, in hypertension and in the inflammatory process [2].
Thus, the main objective of this review is to update the last review, attempting to rationalize the various clinical, physiopathological and/or physiological situations in which LA, through oral supplementation, was tested on human and animal (rats and mice) models, aiming to critically define the plausible health benefits of LA oral supplementation