Insights on the Use of α-Lipoic Acid for

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  Insights on the Use of α-Lipoic Acid for

  Insights on the Use of α-Lipoic Acid for
  Therapeutic Purposes
  Bahare Salehi 1

  , Yakup Berkay Yılmaz 2

  , Gizem Antika 2

  , Tugba Boyunegmez Tumer 3
  ,

  Mohamad Fawzi Mahomoodally 4

  , Devina Lobine 4

  , Muhammad Akram 5
  ,

  Muhammad Riaz 6

  , Esra Capanoglu 7

  , Farukh Sharopov 8,* , Natália Martins 9,10
  ,

  William C. Cho 11,* and Javad Sharifi-Rad 12,*
  1 Student Research Committee, School of Medicine, Bam University of Medical Sciences, Bam 44340847, Iran
  2 Graduate Program of Biomolecular Sciences, Institute of Natural and Applied Sciences,
  Canakkale Onsekiz Mart University, Canakkale 17020, Turkey
  3 Department of Molecular Biology and Genetics, Faculty of Arts and Science,
  Canakkale Onsekiz Mart University, Canakkale 17020, Turkey
  4 Department of Health Sciences; Faculty of Science, University of Mauritius, Réduit 80837, Mauritius
  5 Department of Eastern Medicine, Government College University Faisalabad; Faisalabad 38000, Pakistan
  6 Department of Allied Health Sciences, Sargodha Medical College, University of Sargodha,
  Sargodha 40100, Pakistan
  7 Faculty of Chemical & Metallurgical Engineering, Food Engineering Department, Istanbul Technical
  University, Maslak 34469, Turkey
  8 Department of Pharmaceutical Technology, Avicenna Tajik State Medical University, Rudaki 139,
  Dushanbe 734003, Tajikistan
  9 Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
  10 Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal
  11 Department of Clinical Oncology, Queen Elizabeth Hospital, 30 Gascoigne Road, Hong Kong
  12 Zabol Medicinal Plants Research Center, Zabol University of Medical Sciences, Zabol 61615-585, Iran
  * Correspondence: shfarukh@mail.ru (F.S.); chocs@ha.org.hk (W.C.C.); javad.sharifirad@gmail.com (J.S.-R.)
  Received: 27 June 2019; Accepted: 26 July 2019; Published: 9 August 2019

   

  Abstract: α-lipoic acid (ALA, thioctic acid) is an organosulfur component produced from plants,
  animals, and humans. It has various properties, among them great antioxidant potential and is widely
  used as a racemic drug for diabetic polyneuropathy-associated pain and paresthesia. Naturally, ALA
  is located in mitochondria, where it is used as a cofactor for pyruvate dehydrogenase (PDH) and
  α-ketoglutarate dehydrogenase complexes. Despite its various potentials, ALA therapeutic efficacy
  is relatively low due to its pharmacokinetic profile. Data suggests that ALA has a short half-life
  and bioavailability (about 30%) triggered by its hepatic degradation, reduced solubility as well as
  instability in the stomach. However, the use of various innovative formulations has greatly improved
  ALA bioavailability. The R enantiomer of ALA shows better pharmacokinetic parameters, including
  increased bioavailability as compared to its S enantiomer. Indeed, the use of amphiphilic matrices has
  capability to improve ALA bioavailability and intestinal absorption. Also, ALA’s liquid formulations
  are associated with greater plasma concentration and bioavailability as compared to its solidified
  dosage form. Thus, improved formulations can increase both ALA absorption and bioavailability,
  leading to a raise in therapeutic efficacy. Interestingly, ALA bioavailability will be dependent on age,
  while no difference has been found for gender. The present review aims to provide an updated on
  studies from preclinical to clinical trials assessing ALA’s usages in diabetic patients with neuropathy,
  obesity, central nervous system-related diseases and abnormalities in pregnancy.
  Keywords: α-lipoic acid; bioavailability; formulations; clinical trial; diabetic neuropathy; obesity;
  schizophrenia; sclerosis; pregnancy

  Biomolecules 2019, 9, 356; doi:10.3390/biom9080356 www.mdpi.com/journal/biomolecules

  Biomolecules 2019, 9, 356 2 of 25
  1. Introduction
  α-lipoic acid (ALA), also known as 1,2-dithiolane-3-pentanoic acid or thioctic acid, is a compound
  commonly found in mitochondria, necessary for different enzymatic functions. ALA was isolated by
  Reed in 1951 [1] as an acetate replacing factor and its first clinical use dates from 1959 in the treatment
  of acute poisoning by Amanita phalloides, also known death cap (from mushrooms) [2].
  Briefly, ALA is an organosulfur compound produced from plants, animals, and humans and
  exists in nature. In the Krebs cycle, ALA plays important roles in various chemical reactions, acting
  as a cofactor for some enzymatic complexes involved in energy generation for the cell. It also forms
  covalent bonds with proteins and has therapeutic potential. It has a single chiral center and asymmetric
  carbon which results in two optical isomers: R- and S- lipoic acid (Figure 1) [3]. Thus, ALA has two
  enantiomeric forms, called S and R enantiomers, considered mirror images of each other. Both S and R
  enantiomers are present equally in ALA, being however the R isomeric form present naturally, while
  the S isomer is prepared through chemical processes. Foods are a natural source of the R enantiomer,
  naturally produced inside the living organisms forming covalent bonds with proteins. While ALA
  exists in nature as R enantiomer, synthetic supplementation consists of a racemic composition of R and
  S forms [4]. Although synthetized by the human body at low amount, the ALA quantities produced are
  not enough to fulfill the energy requirement of the cell. Thus, it is mostly obtained from diet, especially
  from meat and vegetables. Fruits are also a source of this acid [5].
  Biomolecules 2019, 9, x 3 of 25
  1.1.1. R-α-Lipoic Acid
  This isomer is present in nature, and is found in animals, plants and from human body. In nature,
  this is the form which ALA demonstrates its effects [23].
  1.1.2. S-α-Lipoic Acid
  This type of isomer is not present in the nature. It may be obtained through many chemical
  procedures of thioctic acid and stops the important activities of R-ALA, e.g., their interaction with
  genes, enzymes and proteins [23].

  R-α-lipoic acid S-α-lipoic acid
  Figure 1. The chemical structure of optical isomers of ALA.

  ALA is found in many vegetables (spinach, broccoli, tomato, brussels sprouts, and rice bran),
  meats and entrails (e.g., liver and kidney) in lipoyllysine form (ALA with binding lysine residues).
  Moreover, ALA can also be synthesized by enzymatic reactions in mitochondria from octanoic acid
  and cysteine (as a sulfur donor) [24,25].
  Both ALA and DHLA have a determinant role in oxidative metabolism [26]. For instance, it has
  been shown that ALA or its reduced form, DHLA have several positive health benefits, including as
  biological antioxidants, metal chelators and detoxification agents, being also able to reduce the
  oxidized forms of other antioxidant agents, including glutathione, vitamins C and E, and to modulate
  various signaling pathways, such as insulin and nuclear factor kappa B (NF-κB) [27]. It has also been
  used for age-associated cardiovascular, cognitive, and neuromuscular deficits [28–30], to reform
  endothelial dysfunction [31], to decrease oxidative stress [32] and to inhibit the formation of
  atherosclerosis plaque [33].
  In this sense, considering the potential therapeutic actions of ALA, we aim to focus on the
  preclinical and clinical studies assessing the ALA pharmacological effects, also considering the
  aspects related with its bioavailability (Figure 2).
  2. Research Methodology
  The search for the above-mentioned bioactive effects and clinical impact of ALA was performed
  in PubMed database, articles published in English were selected, from 2014 to 2019.
  3. α-Lipoic Acid Pharmacological Activities: An Overview
  Over the years, ALA has gained a considerable attention as a food additive with beneficial effects
  both in the treatment or management of several ailments [11,34,35]. ALA’s pharmacological effects
  are primarily related with its antioxidant activity, but ALA and DHLA have also demonstrated
  interesting cardiovascular, cognitive, anti-ageing, detoxifying, anti-inflammatory, anti-cancer, and
  neuroprotective properties [35].

  Figure 1. The chemical structure of optical isomers of ALA.

  On the other hand, ALA has numerous clinically valuable properties [5,6]. It acts as an enzymatic
  cofactor [7] and is also involved in glucose [8,9] and lipid [10] metabolism and manages gene
  transcription. ALA also acts as antioxidant because it not only improves but also restores the intrinsic
  antioxidant systems, and supports their production or cell accessibility [11–13]. It also efficiently
  removes heavy metals from blood stream, responsible for oxidative stress [11,13,14]. The most unique
  characteristic of ALA over other antioxidant substances is that it reacts as both lipid and water soluble
  compound [5,6]. There is no doubt that it is a strong antioxidant, but due to certain reasons its use for
  medicinal purposes is prohibited; however, in some states it is used as a supplement and in others as a
  remedy [5,6,15]. These restrictions are due to some endogenous characteristics of substance by itself,
  such as the changeableness due to the disclosing of dithiolane ring and the emergence of disulfide bond
  between molecules. Other properties that limit the oral use of ALA are its decreased ability to become
  dissolved in the gastrointestinal tract and increased rate of hepatic metabolism. In addition, besides it
  is widely known antioxidant potential, ALA has also many other functions, as it is its involvement in
  mitochondria producing energy, by acting as cofactor for various enzymes involved in metabolism [5].
  Moreover, ALA plays a vital role in glucose humiliation during metabolism. For instance, ALA has
  been applied as a racemic medication for diabetic polyneuropathy-associated pain and paresthesia [16].
  ALA has also an important function in energy transduction through mitochondria [6,17]. Two reduced
  or oxidized thiol groups are present in the small molecule of ALA. The oxidized form is known as
  ALA or simply as lipoic acid, while the reduced form is noted as dihydrolipoic acid (DHLA). ALA
  inactivates free radicals and the reduced form also interacts with reactive oxygen species (ROS) [8].
  Naturally, ALA is found in mitochondria where it binds to the E2 subunit and is used as a cofactor
  for both pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes [18]. ALA is

  Biomolecules 2019, 9, 356 3 of 25
  synthesized de novo at very small amounts in the body from cysteine and fatty acids, because of which
  there is a need to supplement it from exogenous sources [19].
  ALA improves the glycemic control [6], alleviates diabetes mellitus (DM) complications [20,21]
  and even symptoms of peripheral neuropathy, at same time that effectively lessens the heavy metals
  toxicity [22].
  1.1. Forms of Lipoic Acid
  1.1.1. R-α-Lipoic Acid
  This isomer is present in nature, and is found in animals, plants and from human body. In nature,
  this is the form which ALA demonstrates its effects [23].
  1.1.2. S-α-Lipoic Acid
  This type of isomer is not present in the nature. It may be obtained through many chemical
  procedures of thioctic acid and stops the important activities of R-ALA, e.g., their interaction with
  genes, enzymes and proteins [23].
  ALA is found in many vegetables (spinach, broccoli, tomato, brussels sprouts, and rice bran),
  meats and entrails (e.g., liver and kidney) in lipoyllysine form (ALA with binding lysine residues).
  Moreover, ALA can also be synthesized by enzymatic reactions in mitochondria from octanoic acid
  and cysteine (as a sulfur donor) [24,25].
  Both ALA and DHLA have a determinant role in oxidative metabolism [26]. For instance, it has
  been shown that ALA or its reduced form, DHLA have several positive health benefits, including as
  biological antioxidants, metal chelators and detoxification agents, being also able to reduce the oxidized
  forms of other antioxidant agents, including glutathione, vitamins C and E, and to modulate various
  signaling pathways, such as insulin and nuclear factor kappa B (NF-κB) [27]. It has also been used for
  age-associated cardiovascular, cognitive, and neuromuscular deficits [28–30], to reform endothelial
  dysfunction [31], to decrease oxidative stress [32] and to inhibit the formation of atherosclerosis
  plaque [33].
  In this sense, considering the potential therapeutic actions of ALA, we aim to focus on the
  preclinical and clinical studies assessing the ALA pharmacological effects, also considering the aspects
  related with its bioavailability (Figure 2).

  Biomolecules 2019, 9, x 4 of 25

  Figure 2. From preclinical to clinical effects of ALA.

  3.1. α-Lipoic Acid Antioxidant Potential
  There are vast literature data on ALA and DHLA antioxidant effects, namely acting as metal
  chelating agents, free radical scavengers, regenerator of endogenous antioxidants, such as
  glutathione, vitamins C and E and repair of oxidized damage [36]. The existence of thiol groups in
  ALA is responsible for its metal chelating abilities [14,35]. Moreover, it is able to increase the
  glutathione levels inside the cells, that chelate and excrete a wide variety of toxins, especially toxic
  metals from the body [35]. For instance, the study of Goralska et al. [37] showed that ALA
  administration led to a decrease in iron ions in epithelial cells. This change was associated with
  elevated cell resistance to hydrogen peroxide challenge, meaning that ALA exerts a direct impact in
  oxidative stress reduction [37]. Briefly, ALA is conceived as a biological antioxidant that is both
  water- and fat-soluble and is capable to neutralize ROS everywhere in the body, inside and outside
  the cells, and for this reason, ALA is being referred as the universal antioxidant [38–40].
  3.2. α-Lipoic Acid Antidiabetic Potential
  Among the metabolic disorders, diabetes mellitus (DM) represent a serious health problem,
  currently affecting approximately 422-million people worldwide [41]. It is designated by
  disturbances on carbohydrates, lipids, and proteins metabolism [42]. Also, it has been recognized as
  a major risk factor for the development of several human diseases, including atherosclerosis,
  hypertension, heart failure, myocardial infarction, neuropathic pain and even stroke [43]. Emerging
  evidences demonstrate that DM results from the excessive ROS generation and impairment of the
  Figure 2. From preclinical to clinical effects of ALA.

  Biomolecules 2019, 9, 356 4 of 25
  2. Research Methodology
  The search for the above-mentioned bioactive effects and clinical impact of ALA was performed
  in PubMed database, articles published in English were selected, from 2014 to 2019.
  3. α-Lipoic Acid Pharmacological Activities: An Overview
  Over the years, ALA has gained a considerable attention as a food additive with beneficial effects
  both in the treatment or management of several ailments [11,34,35]. ALA’s pharmacological effects are
  primarily related with its antioxidant activity, but ALA and DHLA have also demonstrated interesting
  cardiovascular, cognitive, anti-ageing, detoxifying, anti-inflammatory, anti-cancer, and neuroprotective
  properties [35].
  3.1. α-Lipoic Acid Antioxidant Potential
  There are vast literature data on ALA and DHLA antioxidant effects, namely acting as metal
  chelating agents, free radical scavengers, regenerator of endogenous antioxidants, such as glutathione,
  vitamins C and E and repair of oxidized damage [36]. The existence of thiol groups in ALA is responsible
  for its metal chelating abilities [14,35]. Moreover, it is able to increase the glutathione levels inside the
  cells, that chelate and excrete a wide variety of toxins, especially toxic metals from the body [35]. For
  instance, the study of Goralska et al. [37] showed that ALA administration led to a decrease in iron
  ions in epithelial cells. This change was associated with elevated cell resistance to hydrogen peroxide
  challenge, meaning that ALA exerts a direct impact in oxidative stress reduction [37]. Briefly, ALA is
  conceived as a biological antioxidant that is both water- and fat-soluble and is capable to neutralize
  ROS everywhere in the body, inside and outside the cells, and for this reason, ALA is being referred as
  the universal antioxidant [38–40].
  3.2. α-Lipoic Acid Antidiabetic Potential
  Among the metabolic disorders, diabetes mellitus (DM) represent a serious health problem,
  currently affecting approximately 422-million people worldwide [41]. It is designated by disturbances
  on carbohydrates, lipids, and proteins metabolism [42]. Also, it has been recognized as a major risk
  factor for the development of several human diseases, including atherosclerosis, hypertension, heart
  failure, myocardial infarction, neuropathic pain and even stroke [43]. Emerging evidences demonstrate
  that DM results from the excessive ROS generation and impairment of the antioxidant potential [44–46].
  Several studies have highlighted the potential use of ALA in diabetes, due to its ability to increasing
  both sugar uptake in insulin-sensitive and insulin-resistant muscle tissues [4,47], and to stimulate
  the glucose uptake by the repartition of glucose transporters to the plasma membrane, and tyrosine
  phosphorylation of insulin receptor substrate-1 [9].
  3.3. α-Lipoic Acid and Alzheimer’s Disease
  Alzheimer’s disease (AD) is a neurological disease characterized by cognitive, functional, and
  behavioral alterations. Memory loss has been linked to the formation of beta-amyloid plaques and the
  uprise of tau in a pathological form in patients with AD [48,49]. Substantial evidences have supported
  the implication of oxidative stress in the pathogenesis of AD [50–52]. Non-steroidal anti-inflammatory
  drugs (NSAIDs) have been proposed for the therapy of neurodegenerative diseases, including AD.
  However, the prolonged NSAIDs administration results in gastrointestinal toxicity due cyclooxygenase
  (COX) inhibition [35,53]. To overcome this limitation, ALA has been selected based on the intended
  role of oxidative stress in the development of AD.
  In vitro investigations have indicated that ALA has neuroprotective effects on Aβ-mediated
  cytotoxicity [54–56], namely through defending cortical neurons from cytotoxicity induced by Aβ or
  H2O2 [57], partially attributed to the activation of PKB/Akt signaling pathway. Another study revealed

  Biomolecules 2019, 9, 356 5 of 25
  that ALA has ability to effectively protect cultured hippocampal neurons against both Aβ peptide and
  Fe/H2O2 mediated toxicity [58].
  Studies have also shown that ALA show anti-dementia or anti-AD properties by increasing
  acetylcholine (ACh) production through activation of choline acetyltransferase, which increases
  glucose absorption and, hence, supply more acetyl-CoA for ACh production [59]. Haugaard and Levin
  (2000) reported that DHLA significantly increased the activity of a purified preparation of choline
  acetyltransferase, and that its removal by dialysis from a partially purified of choline acetyltransferase
  led to a complete disappearance of enzyme activity and that its addition restores activity towards
  normal levels. The same finding was obtained when the experiments were repeated with extracts of
  rat brain and heart as well as rabbit bladder tissue. Thus, the authors concluded that it may act as a
  coenzyme in the choline acetyltransferase reaction [60].
  On the other hand, inflammation has a key function in AD. It is engaged around amyloid plaques,
  surrounded by activated astrocytes and microglia, and is characterized by elevated levels of free radicals
  and pro-inflammatory cytokines [61], with TNF-α being considered an indicator from mild cognitive
  impairment to AD [59,62]. ALA has multiple and complex effects in this way, namely scavenging
  ROS, transition metal ions, increasing the levels of reduced glutathione [59,63], scavenging of lipid
  peroxidation products [62,64,65] and even acting on signal transduction pathways [63,66]. Similarly,
  Dinicola et al. [67] found that ALA downregulated the levels of the inflammatory cytokines IL-1B
  and IL-6 in SK-N-BE human neuroblastoma cells through DNA methylation-dependent modulation,
  paving the way for the impact of epigenetic mechanisms in AD control/prevention.
  3.4. α-Lipoic Acid and Cancer
  An increasing body of literature highlight on the potential application of ALA in cancer
  therapy [68,69]. Cancer cells convert glucose preferentially to lactate for ATP generation, a phenomenon
  known as the Warburg effect or aerobic glycolysis. The persistent activation of aerobic glycolysis
  in cancerous cells lead to oncogenes activation or loss of tumor suppressors, thereby causing
  cancer progression. In this respect, the inhibition of aerobic cycle may contribute to anticancer
  effects [70,71]. Pyruvate dehydrogenase catalyzes pyruvate to acetyl CoA conversion, thus preventing
  lactate production. Feuerecker et al. investigated whether ALA is capable of activating pyruvate
  dehydrogenase in tumor cells. The results show that ALA inhibited cell proliferation, [18F]-FDG
  uptake and lactate formation and increased apoptosis in neuroblastoma cell lines Kelly, SK-N-SH,
  Neuro-2a and in the breast cancer cell line SkBr3. In the mouse xenograft model with subcutaneously
  SkBr3 cells, daily treatment with ALA has delayed tumor growth [72].
  ALA suppressed thyroid cancer cell proliferation and growth through activation of AMPK and
  subsequent down-regulation of mTOR-S6 signaling pathway in BCPAP, HTH-83, CAL-62 and FTC-133
  cells lines. In the same study, it was also found that ALA also significantly inhibited tumor growth in
  mouse xenograft model using BCPAP and FTC-133 cells [73]. In lung cancer cells, ALA inhibited cell
  proliferation through Grb2-mediated EGFR down-regulation [74].
  Studies have also shown that ALA is able to generate ROS, which promote ALA-dependent cell
  death in lung cancer [75], breast cancer [76] and colon cancer [77,78], suggesting that it triggers the
  mitochondrial pathway of apoptosis in cancer cells. Recently, the effects of ALA on the migration
  and invasion of breast cancer cells were assessed [79]. The results have showed that ALA inhibited
  metastatic breast cancer cells migration and invasion, partly through ERK1/2 and AKT signaling.
  In summary, the scientific data show that ALA could be applied for cancer management and prevention.
  4. Preclinical Actability of α-Lipoic Acid
  4.1. Anti-diabetic Properties of α-Lipoic Acid
  As previously noted, ALA have shown to be useful for increasing sugar uptake in insulin-sensitive
  and insulin-resistant muscle tissues [4,47]. In addition, the triglycerides’ storage in the body led to

  Biomolecules 2019, 9, 356 6 of 25
  type-2 DM progression. When activated, AMP-activated protein kinase (AMPK) increase sugar uptake,
  fatty acids oxidation and mitochondrial biogenesis. In obese rats, muscle AMPK levels are reduced.
  However, when these rats were submitted to ALA administration, a raise in insulin-stimulated glucose
  disposal in skeletal muscle and in the whole body was observed. ALA was also found to increase lipid
  oxidation and activated AMPK. These results suggest that ALA ameliorate insulin sensitivity through
  AMPK activation [80]. Konrad et al. [9] have demonstrated that ALA stimulates glucose uptake by the
  repartition of glucose transporters to the plasma membrane, and tyrosine phosphorylation of insulin
  receptor substrate-1. In a study carried out by Bitar et al. [81] it was found that the intake of 50 mg/kg
  for 30 days averted diabetes-mediated mitochondrial and endothelial dysfunction in rats, via a signal
  transduction pathway. It is known that in DM, the NO bioavailability is reduced through modulation
  of the endothelial nitric oxide synthase (eNOS) activity and oxidative stress [82]. In endothelial cells of
  aged rats, ALA intake resulted in a decrease in eNOS phosphorylation through Akt [83]. ALA is able
  to trigger Akt phosphorylation in human umbilical vascular endothelial cells and in THP-1 human
  monocyte cell lines [84,85]. These findings propose that the improved endothelial function due to ALA
  is partially ascribed to eNOS recoupling and increased NO bioavailability [82]. Thus, the use of ALA
  as an adjuvant in DM management is related to its capability to inhibit glycation which generates free
  radicals [82,86,87]. Overall, the information amassed herein indicated the potential therapeutic value
  of ALA for the treatment of DM.
  4.2. α-Lipoic Acid and Alzheimer’s Disease
  Given the above highlighted aspects on the use of ALA for neurodegenerative conditions,
  specifically in AD, Quinn et al. [88] assessed the effect of a diet supplemented with ALA on
  hippocampus-dependent memory of aged Tg2576 mice with AD. The authors found that ALA
  led to a marked improvement in learning and memory retention [88], and no significant differences
  were found in β-amyloid levels between ALA-treated and untreated Tg2576 mice [89].
  4.3. α-Lipoic Acid and Pregnancy
  Considering the promising antioxidant potential of ALA and its impact in multiple inflammatory
  conditions, recent evidences have increasingly highlighted its impact in physiological processes, such as
  pregnancy. Interestingly, Micili et al. [90] assessed the impact of ALA vaginal administration in female
  Wistar rats, namely testing its tissue distribution, impact on implantation process and effectiveness in
  contrasting induced preterm birth. Curiously, the authors found that vaginal ALA is well-absorbed
  and distributed, without affecting the implantation process and was even able to significantly revert
  mifepristone plus prostaglandin E2 effects, thus, delaying the delivery timing and decreasing the
  synthesis of mRNA and pro-inflammatory cytokines release [90].
  5. Pharmacokinetics of α-Lipoic Acid
  Although ALA has various biological activities, studies have reported a limited therapeutic
  efficacy due to its pharmacokinetic profile. Data suggests a short half-life and bioavailability of about
  30% due to certain mechanisms, including hepatic degradation, reduced solubility as well as instability
  in the stomach [91]. However, this has been greatly improved through the use of various innovative
  formulations that directly increase ALA bioavailability.
  5.1. Bioavailability of Lipoic Acid Through Food Sources
  In plasma and human cells, the amount of ALA is not enough to meet bodily needs, unless we
  take it through diet. The oral intake of ALA through diet has significantly increased its amount to
  fulfill the energy requirement of the body. Studies have reported a 40% increase in ALA absorption
  when ingested the mixture of both R and S isomers orally during fasting (empty stomach), while a 20%
  reduction of this acid occurs when taken through food sources. The efficacy of ALA R isomer shows
  more stability in plasma and is properly absorbed.

  Biomolecules 2019, 9, 356 7 of 25
  A study suggests that ALA bioavailability is greatly reduced after food intake and it has been
  recommended that ALA should be admitted at least 2 h after eating or if taken before; meal should be
  taken at least 30 min after ALA administration [92]. In addition, it has been suggested that acidic pH
  of the stomach is favorable for ALA absorption through the gastrum. Therefore, ALA supplements are
  preferably taken on an empty stomach to benefit of the acidic stomach pH. Moreover, it also reduces
  ALA competition with other nutrients for absorption [91]. Severe renal damages, as well as food intake,
  influences ALA pharmacokinetic parameters [93,94]. ALA can be taken through diet to fulfill its bodily
  requirements and can be received from natural sources. As previously highlighted, in animals, ALA is
  found in red meat, kidney, liver, and heart of animals, while in plants it is found abundantly in spinach,
  tomatoes, broccoli, brussels sprouts, garden peas, potatoes, and rice bran [11].
  5.2. Lipoic Acid Absorption and Plasma Concentrations
  It was observed that ALA is rapidly absorbed after oral ingestion of 50 to 600 mg thioctic acid.
  The time required to reach the maximum plasma concentrations was about 0.5 to 1 h. Moreover,
  the maximum plasma concentrations of R enantiomer were found to be 40 to 50 percent higher than
  the S enantiomer [95]. The R enantiomer of lipoic acid (RLA) was more rapidly absorbed through
  the intestine when given as an inclusion complex with γ-cyclodextrins. RLA/γ-cyclodextrins (CD)
  exhibit increased plasma exposure when compared to that of non-included R-lipoic acid. Moreover,
  the area under the plasma concentration-time curve (AUC) was 2.2 times higher than that of the
  non-included RLA orally administered, and 5.1 times higher when administered intraduodenally.
  Moreover, the absorption was not affected, even due to administration of an amylase inhibitor during
  the process and ligation of the bile duct [96]. In another work, carried out to assess the absorption
  of a racemic ALA formulation of 600 mg, it was found that ALA takes very little time to reach the
  maximum plasma concentrations of 6.86 ± 1.29 μg/mL.
  It has been noted that plasma RLA concentration is higher than that of SLA at similar doses in
  humans [93]. A recent study performed in rats supports similar results for maximum plasma levels,
  as well as the AUC being almost 1.26 times higher for RLA compared to SLA [97]. Some researchers
  have reported that the rate of ALA uptake is not affected by the time the stomach is emptied, as found
  in a study conducted in insulin-dependent diabetic patients, in whom no particular effect on ALA
  bioavailability was observed [93].
  5.3. Effect of Different Formulations on Lipoic acid Bioavailability
  One study used 18 subjects of both genders, including 9 females and 9 males, and pharmacokinetic
  parameters were observed to assess the bioavailability of ALA in these subjects. Maximum concentration
  of ALA in plasma, time of maximum concentration beyond the terminal ALA half-life were observed
  and recorded in the study of Mignini et al. [98]. Since ALA is poorly soluble, lecithin has been used as
  an amphiphilic matrix to enhance its bioavailability. Tablets and soft gel capsules of ALA at a dose
  of 600 mg had the same bioavailability and other pharmacokinetic parameters, but were higher than
  those of the normally less soluble supplementation of ALA when administered to the human body [98].
  It can be determined that the high bioavailability of ALA, as well as its homogenous release in vivo
  and high content can be increased by increasing its solubility through the use of amphiphilic matrices.
  Similarly, another study determined the ALA bioavailability through different oral and intravenous
  (IV) formulations. The study used 200 mg ALA through the two administration routes to determine
  the pharmacokinetic parameters of ALA. The IV solution was given over 4 min, while the oral one
  consisted of 317.6 mg trometanlole salt, which corresponded to 200 mg of free ALA, 4 tablets of
  50 mg and 1 tablet of 200 mg, given to 12 healthy subjects. The IV solution was the same as the oral
  solution. ALA could be detected for up to 2 h after IV drug administration and for up to 4 h after oral
  administration. However, it was determined that the maximum plasma concentration of ALA was
  greater through the IV route when compared to oral administration; in addition, the terminal half-lives
  for both routes were comparable. A previous study reported that the bioavailability of the R isomer

  Biomolecules 2019, 9, 356 8 of 25
  was greater than that of the S isomer for all oral administrations, while the bioavailability of the R
  isomer was maximal through oral solution [93].
  It has been suggested that ALA bioavailability is markedly increased when orally administered in
  the liquid form rather than a solid dosage form. Moreover, it presents prolonged stability, high plasma
  concentrations and accelerated absorption of ALA [5,7].
  5.4. Age- and Gender-Dependent α-Lipoic Acid Bioavailability
  Age greatly affects both ALA bioavailability and maximum plasma concentrations. Indeed,
  the bioavailability and peak plasma concentrations of ALA were found to be considerably higher in
  adults with mean age greater than 75 years as compared to young adults between the ages of 18 and
  45 years. However, no significant variation in ALA bioavailability was found between males and
  females [17].
  Another study demonstrated similar outcomes, with the exception that in tablet formulation
  (600 mg), the plasma concentrations of both ALA enantiomers were higher in females than males. At
  low concentration, no significant differences were stated [99].
  6. α-Lipoic Acid in Clinical Trials
  ALA has been extensively studied since the 1950’s, when its antioxidant properties were first
  discovered [100]. It has been demonstrated that ALA is effective in relieving some symptoms related to
  certain diseases, such as diabetes, age-related cardiovascular and neuromuscular defects, antipsychotic
  drugs-related weight gain and metabolic obesity [29,89,101,102]. Its potential effects on different types
  of diseases have drawn attention, since the results from studies were promising, namely in the field
  of neurodegenerative conditions [103]. In addition, the number of clinical trials increased to deepen
  knowledge on other ALA therapeutic properties and found hopeful effects.
  6.1. The Effects of α-Lipoic Acid on Diabetic Patients with Neuropathy
  According to the World Health Organization (WHO), the number of diabetic individuals increased
  from 108 million in 1980 to 422 million in 2014; and in 2016, it was estimated that 1.6 million deaths were
  directly caused by diabetes [41,104]. Diabetes consists of a group of diseases caused by hyperglycemia
  and the effects of this condition fall into two major categories: macrovascular and microvascular
  complications. Retinopathy, nephropathy, and neuropathy are well-characterized microvascular
  complications, and the development of neuropathy is closely related to the extent and duration of
  hyperglycemia [105]. Diabetic neuropathy has also been recognized as a major cause of morbidity and
  mortality [106].
  Effects of ALA on diabetes-associated neuropathy have been demonstrated by numerous
  clinical trials (Table 1). In the randomized, double-blind, placebo-controlled, multicenter,
  two-arm, parallel-group trial by Ziegler et al. [107], ALA was shown to be effective against
  mild-to-moderate diabetic sensorimotor polyneuropathy (DSPN). The treatment of diabetic patients
  with mild-to-moderate DSPN with 600 mg of ALA per day orally increased the neuropathy impairment
  score of lower limbs (NIS-LL) after four years. Increased NISS-LL scores greater than 2 were defined as
  a meaningful progression during the trial. All statistical analysis was measured in various subgroups of
  treatment groups. Among all subgroups, baseline subcategories with body mass index (BMI) lower than
  30 kg/m2
  , patients with type 1 diabetes, clinically relevant smokers, and angiotensin-converting-enzyme
  (ACE) inhibitor-treated subgroups showed mean improvement (more than −1 point) in NIS-LL in
  ALA-treated group after 4 years. Subgroups including male patients older than 55 years-old, who
  have cardiovascular disease history and neuropathy more than 3 years with DSPN stage 2a showed a
  remarkable increase in NIS-LL in ALA-treated group when compared to placebo group. In this trial,
  it was shown that ALA might have the potential to prevent the neuropathic impairments progression
  with regular long-term administration. However, this trial was based on mild-to-moderate DSPN and

  Biomolecules 2019, 9, 356 9 of 25
  may not be generalized. Further studies, including more severe stages of DSPN are needed to confirm
  these suggestions.

  Table 1. Effects of ALA in diabetic patients with neuropathy.

  Patients (n) Design Treatment Key Effects References
  Diabetic patients
  with
  mild-to-moderate
  polyneuropathy
  Age range: n.s.
  n = 429

  Clinical trial
  Randomized
  Double-blind
  Placebo-controlled
  Multicenter
  Two-arm

  600 mg/day ALA or
  placebo, orally
  Duration: 4 years

  – Prevention of
  neuropathic
  improvements
  progression with
  regular and
  long-term
  administration

  [107]

  Type 2 diabetic
  patients with
  symptomatic
  polyneuropathy
  Age range: n.s.
  n = 45

  Clinical trial
  Randomized
  Withdrawal
  Open-label study

  600 mg ALA 3
  times per day in
  phase 1, orally
  600 mg ALA daily
  or ALA
  withdrawal in
  phase 2, orally
  Duration: 4 weeks
  (phase 1)
  16 weeks (phase 2)

  – Phase 1: Total
  Symptom Score
  (TSS) decreased
  – Phase 2: TSS
  decreased in
  ALA-treated group
  and improved
  neuropathic
  symptoms

  [108]

  Diabetic patients
  with early
  nephropathy
  Age range: n.s.
  n = 62

  Clinical trial
  Randomized
  Controlled

  600 mg/day ALA,
  intravenously with
  routine treatment
  or routine
  treatment (control
  group)
  Duration: 8 weeks

  – Decline in urinary
  albumin excretion
  rates, serum
  creatinine and
  malonaldehyde
  – Increased plasma
  SOD activity and
  improved
  endothelium-dependent
  flow mediated
  vasodilation
  flexibility

  [102]

  Diabetic patients
  with neuropathy
  Age range: 18–75
  n = 72

  Clinical trial
  Clinical report
  Interventional
  study

  600 mg/day ALA,
  orally
  Duration: 40 days

  – Reduction in
  neuropathic
  symptoms and
  triglycerides levels

  [109]

  In a randomized, open-label trial, ALA activities were investigated in two consecutive phases [108].
  Forty-five diabetes and symptomatic polyneuropathy patients were involved in phase 1 study. All
  participants received 600 mg ALA orally per day for 4 weeks and were instructed not to receive any
  drug that relieves neuropathic pain. Not all of the 45 patients completed the phase 1 because of
  patient withdrawal for personal reasons and use of prohibited drugs. After 4 weeks, patients with
  a Total Symptom Score (TSS) reduction more than 3 points were compared to their baseline value
  and continued to phase 2, where participants were randomly divided into two groups: one group
  continued ALA administration and the other one did not (control) for 16 weeks. The endpoint for
  phase 2 was the change in TSS, including burning and lancinating pain, paresthesias, and numbness.
  At the end of phase 2, TSS decreased in the ALA group, while no changes were stated to the control
  group. Furthermore, burning pain and paresthesias declined from randomization process to end of
  the trial; however, lancinating pain and numbness did not change in ALA-treated group in phase 2.
  Also, the use of analgesic rescue medication (for alleviating pain) was lower in the ALA-treated group.
  Thus, this trial showed that ALA improved neuropathic symptoms, while reducing the use of rescue
  medication in type 2 diabetes patients with symptomatic polyneuropathy.

  Biomolecules 2019, 9, 356 10 of 25
  In the trial by Sun et al. [102], a two-stage randomized, controlled study was conducted. In the first
  stage, 62 patients with early-stage diabetic nephropathy were separated into control and ALA-treated
  groups. Both groups continued to receive regular hypoglycemic therapy (routine treatment) and strict
  diet; however, they were not given ACE inhibitors. In the ALA-treated group, patients received 600 mg
  ALA per day intravenously for 2 weeks. In the second stage, 21 different patients were recruited for
  the study and divided into two groups: normoalbuminuria (urinary albumin excretion rates (UAER)
  lower than 30 mg/24 h) and microalbuminuria (UAER 30–300 mg/24 h). During the study, only one
  patient had side effects (mild nausea). Exosomes quality in urine samples were assessed by electron
  microscopy. Serum creatinine and malondialdehyde levels, as well as UAER were decreased in ALA
  group. Analysis of flow-mediated vasodilation (FMD) with several parameters showed a positive
  correlation only with superoxide dismutase (SOD) activity. Also, it was shown that expression levels
  of CD63-positive exosome were higher in ALA-treated group. This trial reported that in the early
  diabetic neuropathy, ALA could prevent the kidney from general oxidative stress in short-term use.
  Recently, a 40-day prospective, interventional trial by Agathos et al. [109] studied the action of ALA
  (600 mg/day, orally administered) on 72 diabetic patients with neuropathy, who were simultaneously
  taking their prescribed diabetic medications. Patients were scheduled to have 2 visits in 40 days: one
  at the beginning of the trial (baseline) and on the fortieth day (end day). In addition, blood samples
  were also collected to obtain baseline and second visit values. According to questionnaires results,
  neuropathy symptoms were reduced between the two visits. In laboratory results, mean fasting
  triglyceride levels were reduced significantly, whereas other parameters did not change between the
  two visits. Here, it was shown that ALA intake enhanced the quality of life of patients with diabetic
  neuropathy, reduced major symptoms and triglycerides levels.
  6.2. Effects of α-Lipoic Acid in Overweight/Obese Patients
  Obesity is a complex disorder, consisting in an abnormal fat storage that may lead to serious
  pathological diseases, not only in adults but also in children. WHO global estimates showed that the rate
  of obesity has nearly tripled between 1975 and 2016 [110]. Additionally, overweight (BMI 25-< 30) and
  obese (BMI ≥ 30) people have a significantly higher risk for increased mortality from diabetes, kidney
  and cardiovascular diseases and obesity-related cancers [111]. Moreover, the dysfunctional adipose
  tissue is a major merging factor between obesity and other secondary chronic diseases or carcinogenesis
  as a result of insulin resistance, chronic inflammation and altered adipokines secretion [112]. Thus,
  understanding the biology of weight regulation is crucial to discover effective interventional therapies
  for obesity and obesity-related disorders. In addition to the classical and known therapy for obesity,
  which consists of a combination of low-calorie diets and physical activity, researchers are increasingly
  exploiting new promising nutrient supplements to interrupt the cumulative risk of obesity [113].
  Recently, the effects of ALA on weight control has been investigated by clinical trials, resulting in
  promising results worth to mention (Table 2).
  In the study of Huerta et al. [114], 77 healthy overweight/obese women with BMI values between
  27.5 and 40 kg/m2 were studied. All participants were randomly divided into 4 groups, treated with
  1300 mg eicosapentaenoic acid (EPA) or 300 mg of ALA or 1300 mg of EPA plus 300 mg of ALA or
  placebo daily for 10 weeks. All individuals were adapted to 30% energy-restricted diet during this
  period. Accordingly, the ALA treated group showed significantly higher body weight loss and an
  important drop in leptin levels from the first week of treatment, despite no significant decrease in
  their resting metabolic rate was stated. A notable drop in triglycerides levels and diastolic blood
  pressure (DBP) was found in EPA plus ALA supplemented group. In general, all groups, except EPA
  supplemented one, had a significant reduction in leptin levels and marked improvements in insulin
  level during the oral glucose tolerance test (OGTT). No unfavorable effects were stated in the clinical
  trial period.

  Biomolecules 2019, 9, 356 11 of 25

  Table 2. Effects of ALA in overweight/obese patients.

  Patients (n) Design Treatment Key Effects References
  Overweight/
  obese women
  Age range: 20–50
  n = 77

  Clinical trial
  Randomized
  Double-blind
  Placebo-Controlled
  Parallel design

  1300 mg/day EPA or
  300 mg/day ALA or
  both 1300 mg/day EPA
  + 300 mg/day ALA or
  placebo, orally
  30% energy-restricted
  diet
  Duration: 10 weeks

  – Significantly higher
  body weight loss in
  ALA treated groups
  – Significantly
  attenuated decrease
  in leptin levels in
  ALA treated groups
  during weight loss

  [114]

  Overweight/
  obese women
  Age range: 20–50
  n = 73

  Clinical trial
  Randomized
  Double-blind
  Placebo-controlled
  Parallel design

  1300 mg/day EPA or
  300 mg/day ALA or
  both 1300 mg/day EPA
  + 300 mg/day ALA or
  placebo
  30% energy-restricted
  diet
  Duration: 10 weeks

  – A high reduction in
  body weight, BMI
  and fat mass was
  stated in ALA treated
  groups
  – Significant
  reduction in glucose
  levels for only
  control group and
  EPA + ALA group
  – No significant
  differences in irisin
  changes between
  groups

  [114]

  Overweight or
  obese patients
  Age range: 38–47
  n = 170

  Clinical trial
  Single-center
  Randomized
  Double-blind
  Crossover
  controlled

  1200 mg/day ALA or
  placebo, orally
  Duration: 8 weeks

  – Significant
  reduction in body
  weight and waist
  circumference

  [115]

  Obese patients
  with non-alcoholic
  fatty liver disease
  (NAFLD)
  Age range: 20–50
  n = 45

  Clinical trial
  Randomized
  Double-blind
  Placebo-controlled

  1200 mg/day ALA +
  400 mg/day vitamin E
  or vitamin E (placebo),
  orally
  Duration: 12 weeks

  – Significant
  improvement in
  serum adiponectin
  and IL-6 levels

  [116]

  Overweight/obese
  women
  Age range: not
  specified
  n = 57

  Clinical trial
  Randomized
  Double-blind
  Placebo-controlled

  300 mg/day ALA or
  1300 mg/day EPA or
  1300 mg/day EPA +
  300 mg/day ALA or
  placebo, orally
  Hypocaloric diet
  Duration: 10 weeks

  – A significant
  reduction in the
  circulating levels of
  saturated fatty acid
  and total n-6-PUFAs
  [113]

  Overweight/
  obese sedentary
  females
  Age range: n.s.
  n = 65

  Clinical trial
  Randomized
  Double-blind
  Placebo-controlled

  300 mg/day ALA or
  1300 mg/day EPA or
  1300 mg/day EPA +
  300 mg/day ALA or
  placebo, orally
  Energy restricted diet
  Duration: 10 weeks

  – Significant
  reduction in BMI and
  fat mass in ALA
  treated groups

  [117]

  Huerta et al. [114] also investigated the potential relationship between circulating irisin and
  glucose metabolism and the effects of ALA or EPA on them. Irisin is a myokine; however, its role
  in obesity is not clear so far. A randomized, placebo-controlled, double-blind clinical trial with
  parallel design was conducted on 73 healthy overweight or obese women. The treatment groups
  design, supplementation doses for EPA, ALA, and the combination of EPA/ALA were identical to the
  above-mentioned research. Blood glucose levels demonstrated a significant decrease only in the control
  group and in the group of EPA and ALA combination. A considerably high significant reduction in
  body weight, hip circumference and fat mass were reported in ALA supplemented groups as compared
  to control and only EPA-treated groups. After weight loss, all groups showed decrease in irisin level;
  however, its concentration did not demonstrate significant differences between groups. Moreover,

  Biomolecules 2019, 9, 356 12 of 25
  the analyses of changes in irisin level did not show significant correlation with weight loss, fat mass,
  and fat-free mass after 10 weeks of intervention, except for changes in insulin levels, which had positive
  relation. No substantial effects of ALA administration were obtained for irisin levels reduction in obese
  subjects. Therefore, more clinical interventions are needed in obese patients to clinically prove the
  effect of ALA in irisin production.
  In another study, Li et al. [115] investigated the action of ALA therapy on body weight, waist
  circumference, and lipid metabolism in one hundred seventy overweight or obese patients (BMI ≥25
  kg/m2
  ). ALA group received orally 1200 mg ALA per day for 8 weeks, then after a 4-week washout
  intervention this group continued to receive placebo for 8 weeks. The exact opposite sequence of
  ALA and placebo interventions was used for placebo group. According to mixed model statistical
  analysis, ALA administration showed a significant body weight and waist circumference reduction.
  However, no significant differences found to leptin levels, lipid profile and adverse effects between the
  two groups. Only one female subject had severe nettle-rash in the ALA group.
  Hosseinpour-Arjmand et al. [116] assessed the effect of ALA on liver enzymes and inflammatory
  markers for non-alcoholic fatty liver disease (NAFLD), which is highly cooperating with the
  inflammatory components of obesity. A clinical trial was carried out on 45 obese patients with
  NAFLD, who received 1200 mg ALA plus 400 mg vitamin E or placebo involving 400 mg vitamin E
  per day for 12 weeks. ALA supplementation resulted in a notable increase in serum adiponectin levels
  and a reduction in IL-6 as well as insulin levels compared to placebo. Significant improvement in liver
  steatosis grade was detected for both ALA treated group (91.3%) and placebo group (54.5%) compared
  to their baseline value; however, changes were not statistically different between two groups. In the
  trial, the results indicated that 1200 mg of ALA supplementation per day was well-tolerated without
  any adverse effect.
  In the study of Escoté et al. [113], ALA administration was involved in another clinical trial to
  determine the relationship between fibroblast growth factor 21 (FGF21), which play a role as energy
  homeostasis regulator in metabolism and fatty acid profile. Fifty-seven overweight or obese women
  were administered with 1300 mg EPA or 300 mg ALA or 1300 mg EPA plus 300 mg ALA or placebo
  daily according to four different intervention groups with energy-restricted diet for 10 weeks. At the
  end of the trial, no significant relation was found between plasma FGF21 levels and weight loss or
  total fat mass for all experimental groups.
  Romo-Hualde et al. [117] investigated the metabolomic changes occurred with the supplementation
  of 1300 mg EPA or 300 mg ALA or 1300 mg EPA plus 300 mg ALA or placebo per day on 67 healthy
  overweight/obese sedentary females by following an energy-restricted diet for 10 weeks. In this
  study, urine samples were used for pattern recognition and characteristic metabolites identification
  by principal component analysis and partial least squares-discriminant analysis. A higher reduction
  in BMI and fat mass were found for all ALA-supplemented groups compared to EPA-treated and
  placebo groups. Therefore, ALA administration may have beneficial effects on body weight reduction,
  however further studies are warranted.
  6.3. Effects of α-Lipoic Acid on Patients with Schizophrenia
  Schizophrenia is a serious psychiatric and dysfunctional disorder that involves many symptoms.
  Hallucinations, delusions, and many neurocognitive deficits, including attention and memory loss, are
  the well-recognized symptoms [118]. The use of antipsychotic drugs relieves these symptoms to some
  extent [119], but they can also lead to several side effects, such as metabolic syndrome and weight
  gain [120,121]. Herein, trials describing the actions of ALA in schizophrenic patients were summarized
  (Table 3).

  Biomolecules 2019, 9, 356 13 of 25

  Table 3. Effects of ALA in schizophrenic patients.

  Patients (n) Design Treatment Key Effects References
  Schizophrenia with
  antipsychotic
  induced weight gain
  Age range: n.s
  n = 15

  Clinical trial
  Randomized
  Double-blind
  Placebo-controlled

  600–1800 mg/day ALA
  or placebo, orally
  Duration: 12 weeks

  – Reduction in body
  weight and BMI
  – Significantly reduced
  visceral fat areas
  – No severe side effects
  except gastrointestinal
  symptoms and mild
  dermatologic
  symptoms

  [101]

  Schizophrenia
  Age range: 18–60
  n = 10

  Clinical trial
  Open-Label Trial

  100 mg/day ALA,
  orally
  Duration: 4 months

  – Significant
  improvement in
  neurocognitive
  parameters
  – No significant
  differences in BMI,
  abdominal
  circumference, blood
  count and liver
  enzymes

  [122]

  Schizophrenia
  Age range: 25–60
  n = 18

  Clinical trial
  Controlled

  500 mg/day ALA,
  orally
  Duration: 3 months

  – Significant increase in
  plasma adiponectin
  levels
  – Decrease in fasting
  glucose and aspartate
  aminotransferase
  activity

  [123]

  In the clinical trial of Kim et al. [101], 22 patients with schizophrenia were followed for 12 weeks in
  a double-blind, randomized placebo-controlled trial. Patients were divided into ALA-treated (n = 10)
  and placebo (n = 12) groups. Patients continued to use their antipsychotic drugs during the trial. ALA
  was administrated orally per day 30 min before each meal. The ALA dosage started at 1200 mg/day,
  then it was increased if the effect was not sufficient, or decreased if side effects were observed. The
  overall dose range for ALA was between 600–1800 mg/day. The primary outcomes were weight loss
  and decreased BMI in ALA-treated group. Plasma glucose and lipid profiles, as well as abdominal
  fat area by fat computed tomography scan were determined at the first and last day of the trial.
  Accordingly, only visceral fat area was found to be notably distinct between groups; however, no
  significant changes were detected in both sugar and fatty acid profiles. Thus, in this trial, it was shown
  that ALA seems to be effective against antipsychotic drugs-related weight gain. However, only a small
  number of patients was involved in this trial; so, studies with larger patient groups are needed to
  support these findings.
  Vidovi ́c et al. [123] investigated the effects of ALA in 18 patients with schizophrenia to observe
  how plasma adiponectin levels and some metabolic risk factors change in a controlled clinical trial.
  ALA was administrated to all patients at 500 mg/day before breakfast for 3 months and patients
  were advised to continue to their usual dietary habits, antipsychotic drugs, and lifestyle. Blood
  sampling was handled at the beginning (baseline), in the middle and at the end of the trial. Fasting
  glucose, lipid status parameters, and liver enzymes were determined in serum samples. In addition,
  anthropometric measurements were analyzed including weight, height, waist circumference, and
  body fat. It is reported that after ALA treatment for three months, plasma adiponectin levels were
  increased significantly, whereas there were no remarkable changes in other factors. Furthermore, it
  was found a substantial reduction in fasting serum glucose and aspartate aminotransferase activity.
  Thus, this trial suggested that ALA may have a notable effect in the therapy of some metabolic risk
  factors in schizophrenia. Nevertheless, as this trial did not comprise a control group and open-label
  design, randomized controlled trials with larger patient groups are necessary to confirm the findings.

  Biomolecules 2019, 9, 356 14 of 25
  Recently, an open-label trial reported the effects of ALA in 10 patients with stable chronic
  schizophrenia [122]. The trial was conducted for 4 months with supplementation of 100 mg ALA/day
  with simultaneous use of prescribed antipsychotics. There were five visits and psychotic measurements
  were also obtained. At visits 1 and 5, neurocognitive assessments (Trail Making Test, Block Corsi Test,
  Subtest Digit Span, Category (Animal) Fluency and Controlled Oral Word Association Test, COWA
  (FAS test), and Rey Auditory Verbal Learning Test), collection of blood samples, measurement of
  abdominal circumference and body mass index (BMI) were carried out. At least a 25% decrease in
  negative/disorganization symptoms, including excitement (excitement, hostility, tension, grandiosity,
  and uncooperativeness), depression (depressive mood, guilt feelings, and motor retardation) and
  positive symptoms (unusual thought content, suspiciousness, and hallucinatory behavior) were
  observed between the first and last visits. Furthermore, there was a significant improvement in all
  neurocognitive tests, except for the Category (Animal) Fluency and the FAS test. There were no
  significant differences in abdominal circumference, BMI, complete blood count, levels of liver enzymes
  and other parameters. However, new trials with larger groups as well as randomized, double-blind
  and controlled design are needed to get reliable conclusions.
  6.4. Effects of α-Lipoic Acid in Patients with Multiple Sclerosis
  Multiple sclerosis is a known disabling disorder of the central nervous system (CNS) and attributed
  to multicentric inflammation and demyelination of CNS [124]. Inflammation in MS is developed by the
  invasion of T cells into the CNS, then they produce the matrix metalloproteinase-9 (MMP-9), which is
  an important protease correlated with MS relapse. Some studies proposed that ALA may be a useful
  drug for MS due to its inhibitory potential on T cells and inflammatory modulators migration [125,126].
  MS with changing periods of the neurological disorder and recovery periods is described as a
  relapsing-remitting MS (RRMS), which is the most familiar type of MS. Additionally, if the neurological
  damage, such as axonal loss via inflammation-mediated demyelination increases in RRMS patients,
  this disease is often returned into a secondary-progressive disease course (SPMS) or even rarely to
  the primary progressive MS (PPMS). Thus, the attention on improving therapeutic agents to restrain
  progressive phases of MS is expanding in recent years [127]. The effects of ALA in this aspect were
  also investigated through a few number of clinical trials, summarized in Table 4.
  In the study of Khalili et al. [128] the anti-inflammatory effects of daily ALA consumption on RRMS
  patients were investigated. Forty-six patients were randomly separated into ALA group, which received
  1200 mg ALA or placebo group, which received placebo per day for 12 weeks. A remarkable decrease in
  INF-γ, TGF-β, ICAM-1, and IL-4 levels was observed in ALA group when compared with the placebo
  group. However, no notable changes were stated in the levels of some cytokines, including TNF-α,
  IL-6, EDSS, and MMP-9 through ALA administration. Therefore, this study revealed preliminary
  supportive data on the anti-inflammatory effect of ALA on RRMS patients; however, further studies
  were needed with larger patients’ group to confirm these results.
  The therapeutic effects of ALA on gait and balance deterioration, which are two critical symptoms
  for SPMS patients were investigated by Loy et al. [129]. The daily oral administration of 1200 mg ALA
  was examined and compared with placebo on 21 subjects during 2 years and the improvement in
  physical functions was assessed by Timed Up and Go (TUG) and quiet standing tasks in the particular
  periods. As a result, it was reported that ALA-treated patients with less disability showed a significantly
  better turning time in TUG-fast task, which measures the ability of patients how much walking quickly
  compared to the placebo group. Thus, this pilot study enabled an expanded clinical trial of ALA
  treatment for walking impairment in SPMS patients.

  Biomolecules 2019, 9, 356 15 of 25

  Table 4. Effects of ALA in patients with multiple sclerosis (MS).

  Patients (n) Design Treatment Key Effects References
  Relapsing-remitting
  MS
  Age range: 18–50
  n = 52

  Clinical trial
  Randomized
  Double-blind
  Placebo-controlled

  1200 mg/day ALA
  or placebo, orally
  Duration: 12
  weeks

  – Significant reduction
  in serum levels of
  INF-γ, ICAM-1 TGF-β
  and IL-4
  – No significant
  changes in TNF-α, IL-6,
  EDSS and MMP-9
  levels

  [128]

  Secondary progressive
  multiple sclerosis
  (SPMS)
  Age range: 40–70
  n = 21

  Clinical trial
  Randomized
  Double-blind
  Placebo-controlled
  Pilot study

  1200 mg/day ALA
  or placebo, orally
  Duration: 2 years

  – Significant
  improvements in
  walking performance
  in patients

  [129]

  Relapsing and
  remitting MS (RRMS),
  secondary progressive
  MS (SPMS)
  Age range: age ≥ 18
  n = 57

  Clinical trial
  Controlled

  1200 mg racemic
  ALA once
  Duration: 48 h

  – Increased cAMP at 2
  and 4 h of ALA
  treatment in healthy
  and SPMS patients
  – Decrease cAMP in
  RRMS patients

  [130]

  Fiedler et al. [130] designed the first clinical trial to investigate the relationship between ALA
  and cAMP production and also the oral bioavailability of ALA by using healthy control, RRMS, and
  SPMS subjects. This study was completed by 57 subjects who received 1200 mg ALA orally for once.
  Blood probes were taken before and after 1, 2, 3, 4, 24 and 48 h from ALA administration for the
  cAMP measurements and ALA plasma levels by pharmacokinetic analysis. The reason for focusing on
  cAMP in MS patients was its inhibitory effects on proinflammatory cytokines expression and T-cells
  activation. Pharmacokinetics’ of plasma ALA concentration was compared between the healthy control,
  RRMS, and SPMS groups and showed no significant differences for half-life, Tmax, Cmax, volume of
  distribution, and oral clearance parameters. On the other hand, increased cAMP concentration was
  observed in healthy and SPMS subjects at 2 and 4 h of post-ALA treatment compared to baseline. Also,
  the ALA stimulatory effect on cAMP was analyzed by measuring plasma prostaglandin E2 (PGE2)
  levels, which is known as a cAMP stimulator and showed a significantly higher concentration in
  female healthy and SPMS subjects 4 h after ALA taking compared to RRMS subjects. In conclusion,
  these obtained data concluded that although the ALA stimulatory activity on cAMP production was
  divergent in RRMS patients, cAMP could be used as a biomarker to trace the medicinal actions of ALA
  in SPMS patients.
  6.5. Effects of α-Lipoic Acid on Abnormalities in Pregnancy
  Abnormalities in pregnancy, such as intrauterine bleeding or sub-chorionic hematomas are often
  associated with threatened miscarriage, especially during the first trimester of pregnancy. Sub-chorionic
  hematoma is a sonographically detected anechoic area with a falciform shape that increases the risk of
  spontaneous abortion [131]. Placental dysfunction, insufficient angiogenesis, and chronic inflammation
  are underlying causes of early pregnancy bleeding, and these factors can even result in preterm
  labor or perinatal mortality [132]. Progesterone has a significant role both in maturation of fetus and
  cytokine balance. Therefore, administration of progestogens is mostly used to prevent threatened
  miscarriage [133]. On the other hand, ALA treatment has been recently studied by some clinical trials
  to explain its efficacy in preventing miscarriage (Table 5).

  Biomolecules 2019, 9, 356 16 of 25

  Table 5. Effects of ALA on abnormalities in pregnancy.

  Patients (n) Design Treatment Key Effects References

  Threatened
  miscarriage and
  subchorionic
  hematoma
  Age range: 20–40
  n = 16

  Preliminary
  Clinical trial
  Randomized

  600 mg/day ALA +
  400 mg/day
  Progesterone or
  400 mg/day
  Progesterone (control
  group), orally
  Duration: until
  complete resolution of
  the clinical picture

  – Effective
  determination in major
  signs of threatened
  miscarriage in
  ALA-treated group
  – Significant
  improvements for
  hematoma resorption
  in ALA-treated group
  – No adverse effects on
  mother or fetus

  [134]

  Singleton pregnancy, at
  a gestational age
  ranging 24–30 weeks,
  hospitalized for a first
  preterm labor episode
  Age range: n.s.
  n = 32

  Clinical trial
  Randomized
  Placebo-controlled
  Pilot study

  400 mg/day ALA
  (active ingredient
  10 mg) or placebo,
  vaginal tablets
  Duration: 30 days

  – Significant increase in
  anti-inflammatory
  interleukins in the
  cervical vaginal liquids
  of undelivered women
  after a preterm labor
  episode

  [135]

  Threatened
  miscarriage
  Age range: 24–40
  n = 62

  Clinical trial
  Randomized
  Controlled

  10 mg/day ALA
  (vaginal capsule) or
  400 mg/day
  progesterone (vaginal
  soft gel) or placebo
  Duration: 60 days

  – quick reabsorption of
  sub-chorionic
  hematoma in
  ALA-treated group
  – Smaller number of
  miscarriages in
  ALA-treated group

  [136]

  A preliminary randomized clinical trial was done by Porcora et al. [134] to assess the supportive
  action of ALA with progesterone therapy in the recovery of sub-chorionic hematomas on 16 patients
  with threatened miscarriage. The subjects were between 6th and 13th week of pregnancy with pelvic
  pain, vaginal bleeding, and sub-chorionic hematomas. They were randomly divided into two groups.
  Accordingly, both control and case groups were administered with 400 mg progesterone/day in the
  form of vaginal suppositories. Besides, case group was additionally treated with 600 mg ALA/day
  until complete resolution of the clinical picture. Medical examinations of all subjects were carried
  out after a week from the enrollment, and later every fifteen days until the symptoms disappeared.
  During treatment, undesirable effects were not reported either in the mother or fetus. Earlier and
  better improvements in the symptoms of sub-chorionic hematomas were detected in the ALA plus
  progesterone treatment group when compared to progesterone alone. However, the change of soft
  uterus, which is a symptom of threatened miscarriage was not statistically significant in both groups.
  This study may suggest that ALA may be beneficial for health of both mother and fetus in case of
  threatened miscarriage.
  A pilot, randomized, placebo-controlled, parallel group and monocenter study of Grandi et
  al. [135] studied the anti-inflammatory activities of ALA on cervical inflammation and shortening after
  primary tocolysis. Thirty-two women with a singleton pregnancy, at gestational age ranging 24–30
  weeks and hospitalized for a first preterm labor episode were randomly recruited for the intake of
  400 mg/day of ALA in the form of vaginal hard tablets (active ingredient 10 mg) or placebo before
  sleep for 30 days. Their cervical-vaginal fluids were obtained by cervical swab to quantify the levels
  of pro-inflammatory cytokines before and after treatment in both groups. Moreover, cervical length
  tracing [122], whose shortening is a clue for preterm birth, was achieved by transvaginal ultrasound
  method before and after treatment. These analyses showed a notable enhance in both IL4 and IL10
  levels by vaginal ALA treatment compared to placebo, while no remarkable changes were found to
  proinflammatory cytokines ratio between groups. Another important effect of ALA was observed in
  CL measurements. Accordingly, it was reported that the shortening of the cervix was restricted more

  Biomolecules 2019, 9, 356 17 of 25
  effectively in vaginal ALA than in control group. Overall, these results encourage larger randomized
  and controlled clinical trials on this topic.
  In a study, Costantino et al. [136] compared the actions of vaginal ALA or progesterone treatment
  in sub-chorionic hematoma resorption in 62 pregnant women with threatened miscarriage. Two
  treatment groups (1:1 ratio) were defined: one received 400 mg of vaginal progesterone (vaginal soft gel)
  daily or 10 mg of vaginal ALA (vaginal capsule) and one control group without treatment (upon their
  requests) during 60 days. The development of sub-chorionic hematoma was controlled by a vaginal
  ultrasound scan after 20 days and 60 days and no adverse effects on the fetus were recorded. Significant
  improvements and a smaller number of miscarriages were observed for the sub-chorionic hematoma
  resorption in the ALA-treated group, compared to progesterone group. However, no remarkable
  variations were recorded in pelvic pain and vaginal bleeding values in any of the groups. Therefore,
  these primary data support that ALA can be an effective medical route for the treatment of patients
  with threatened miscarriage; nevertheless, more studies are needed to confirm this usage.
  6.6. Other Trials
  There are small numbers of trials assessing the effects of ALA in organ transplantation and in case
  of chemotherapy.
  In the work of Ambrosi et al. [137], the effects of ALA against ischemia-reperfusion injury (IRI)
  which occurred after simultaneous kidney-pancreas transplantation were investigated. Twenty-six
  patients with diabetic polyneuropathy were separated into three groups: no treatment, donor and
  recipient ALA-treated and only recipient ALA-treated groups. 600 mg ALA were administrated
  to ALA-treated groups before surgery. The aims of including two treated groups (recipient
  treated—recipient and donor treated) was to figure out the influence of produced ROS at the different
  stages of IRI. Pancreatic and kidney biopsies were done at the end of the surgery to perform
  polymerase chain reaction (RT-PCR); however, the amount of biopsied tissue was not enough to
  perform immunohistochemical staining. Blood probes were obtained before and after surgery. The
  levels of serum inflammatory cytokines and other measurements were carried out. Low levels of
  TNFα and C3 in kidneys, and high levels of heme oxygenase-1 (HMOX-1) and C3 in the pancreatic
  biopsies were reported. Furthermore, the decrease in IL-8, IL-6, secretory leukocyte protease inhibitor,
  and regenerating islet-derived protein 3 β/pancreatitis-associated protein levels were recorded in the
  donor-recipient treated group. This study showed that ALA can be effective in reducing inflammatory
  markers, kidney dysfunction and clinical pancreatitis in post-transplant patients. However, there
  are few studies including organ transplantation. Thus, there is a need for further randomized,
  placebo-controlled studies to obtain more reliable results on ALA effectiveness.
  Recently, Casciato et al. [138] carried out a clinical trial in 40 liver transplant patients. Patients
  were divided into two groups: ALA-treated and placebo. 600 mg of ALA was administrated to patients
  in the donor portal vein immediately before the cold ischemia time; then, another 600 mg of ALA was
  administrated 15 min prior to the reperfusion. Liver tissue samples were collected from the donor
  and from patient 2 h after reperfusion. Blood probes were taken before and at the end of surgery.
  Samples were collected 5 times in a month after surgery. Biochemical liver parameters were also
  measured. High levels of hypoxia-inducible factor-1 (HIF-1α) and prolyl hydroxylase-2 (PHD2) were
  reported in liver biopsies for ALA-treated group, whereas no significant differences were stated to
  other hypoxia-related parameters. In addition, it was shown that baculoviral IAP repeat containing
  2 (Birc2) transcription levels were also higher in the ALA-treated group. Also, the plasma levels of
  alarmins were lower in ALA-treated patients. Overall, these results suggest that the use of ALA in
  liver transplantation is safe as it can be protective against hypoxia and oxidative stress by inducing
  changes in the gene expressions at the mRNA levels.
  Finally, Guo et al. [139] assessed the effect of ALA on prevention of chemotherapy-induced
  peripheral neuropathy. Forty cancer patients completed the trial. They were divided into two groups:
  ALA-treated and placebo. Further, these groups were separated to three groups according to their

  Biomolecules 2019, 9, 356 18 of 25
  platinum exposure levels. 1800 mg of ALA or placebo were administrated orally every day, except
  during the period 2 days before to 4 days after administration of each dose of platinum to avoid
  potential interference with platinum’s antitumor effects. Neuropathic symptoms were measured at
  baseline and then at 24, 36, and 48 weeks of treatment. Besides, Brief Pain Inventory (BPI) Partial Forms
  (it included three-item questionnaires) were given to patients to learn their pain symptoms during
  the trial. No remarkable changes were recorded between groups for all parameters measured. It was
  concluded that ALA was ineffective against the neurotoxicity induced by the action of oxaliplatin or
  cisplatin, so that it is necessary to conduct future studies.
  7. Conclusions
  ALA has various benefits, including antioxidant potential; however, it has been shown that the
  therapeutic efficacy of ALA is restricted because of limitations related with its pharmacokinetic profile.
  Data shows a short half-life and bioavailability of about 30% of ALA due to mechanisms involving
  hepatic degradation, reduced ALA solubility as well as instability in the stomach. However, the use of
  various innovative formulations has proved to be effective in enhancing ALA bioavailability. It has been
  shown through studies that ALA bioavailability is enhanced through the use of amphiphilic matrices,
  able to enhance its solubility and absorption in the intestine. Moreover, ALA liquid formulations show
  greater plasma concentrations and bioavailability as compared to solid dosages. Moreover, age also
  affects ALA bioavailability, while gender shows insignificant differences. Thus, improved formulations
  that can enhance ALA absorption will markedly improve ALA bioavailability, ultimately leading to an
  improved therapeutic efficacy.
  When looking at data from clinical trials, ALA has revealed to be efficient in particular diseases
  and conditions, including diabetic neuropathy, obesity, schizophrenia, MS, abnormalities in pregnancy
  and organ transplantation, with no or minor adverse effects. ALA seems to be also a promising agent
  to improve quality of life, as well as neuropathic symptoms and even to reduce the use of rescue drugs,
  which are commonly used by patients with diabetic neuropathy. Moreover, it has the potential to
  improve the lipid metabolism and promote weight reduction in obese patients, besides to alleviate
  CNS-related diseases (Schizophrenia and MS) symptoms. ALA may also decrease body mass gain
  caused by the application of prescribed antipsychotic agents, as well as some metabolic risk factors in
  patients with schizophrenia. In patients with MS, ALA has some positive outcomes, especially in the
  enhancement of walking and balance disabilities, while decreasing the levels of some proinflammatory
  factors related to MS progression. Therefore, the clinical trials assessing the ALA effects show its ability
  to alleviate some symptoms, commonly found in CNS diseases, with highly promising results. In case
  of threatened pregnancies, ALA demonstrated beneficial effects on the enhancement of sub-chronic
  hematoma symptoms, as well as positive results in miscarriage prevention, with no adverse effects.
  ALA is also effective in organ transplantation patients by reducing the levels of inflammatory factors
  and exerting protective effects against hypoxia and oxidative stress, whereas in case of neurotoxicity
  caused by cytotoxic chemotherapy medication ALA did not represent a protective function. Taken all
  together, ALA may be classified as one of the candidate molecules for prevention or slowing down
  some conditions associated with several diseases’ progression. However, more controlled and robust
  clinical trials must be designed for investigating ALA therapeutic effects.
  Author Contributions: All authors contributed significantly to this work. In addition, J.S.-R., B.S., N.M., W.C.C.
  and F.S., critically reviewed the manuscript. All authors read and approved the final manuscript.
  Funding: N. Martins would like to thank the Portuguese Foundation for Science and Technology (FCT-Portugal)
  for the Strategic project ref. UID/BIM/04293/2013 and “NORTE2020 – Northern Regional Operational Program”
  (NORTE-01-0145-FEDER-000012).
  Conflicts of Interest: The authors declare no conflicts of interest.

  Biomolecules 2019, 9, 356 19 of 25
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