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: (F.S.); (W.C.C.); (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

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
Age range: n.s.
n = 429

Clinical trial

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

– Prevention of
progression with
regular and


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

Clinical trial
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


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

Clinical trial

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

– Decline in urinary
albumin excretion
rates, serum
creatinine and
– Increased plasma
SOD activity and
flow mediated


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

Clinical trial
Clinical report

600 mg/day ALA,
Duration: 40 days

– Reduction in
symptoms and
triglycerides levels


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
obese women
Age range: 20–50
n = 77

Clinical trial
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
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


obese women
Age range: 20–50
n = 73

Clinical trial
Parallel design

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

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


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

Clinical trial

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

– Significant
reduction in body
weight and waist


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

Clinical trial

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

– Significant
improvement in
serum adiponectin
and IL-6 levels


Age range: not
n = 57

Clinical trial

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

obese sedentary
Age range: n.s.
n = 65

Clinical trial

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


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
). 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
induced weight gain
Age range: n.s
n = 15

Clinical trial

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


Age range: 18–60
n = 10

Clinical trial
Open-Label Trial

100 mg/day ALA,
Duration: 4 months

– Significant
improvement in
– No significant
differences in BMI,
circumference, blood
count and liver


Age range: 25–60
n = 18

Clinical trial

500 mg/day ALA,
Duration: 3 months

– Significant increase in
plasma adiponectin
– Decrease in fasting
glucose and aspartate


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
Age range: 18–50
n = 52

Clinical trial

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

– Significant reduction
in serum levels of
and IL-4
– No significant
changes in TNF-α, IL-6,
EDSS and MMP-9


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

Clinical trial
Pilot study

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

– Significant
improvements in
walking performance
in patients


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

Clinical trial

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


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

miscarriage and
Age range: 20–40
n = 16

Clinical trial

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


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
Pilot study

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

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


Age range: 24–40
n = 62

Clinical trial

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

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


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”
Conflicts of Interest: The authors declare no conflicts of interest.

Biomolecules 2019, 9, 356 19 of 25
1. Reed, L.J.; DeBusk, B.G.; Gunsalus, I.C.; Hornberger, C.S. Crystalline α-lipoic acid: A catalytic agent
associated with pyruvate dehydrogenase. Science 1951, 114, 93–94. [CrossRef] [PubMed]
2. Bock, E.; Schneeweiss, J. Ein Beitrag zur Therapie der Neuropathia diabetica. Munch. Med. Wochenschr. 1959,
43, 1911–1912.
3. Brookes, M.H.; Golding, B.T.; Howes, D.A.; Hudson, A.T. Proof that the absolute configuration of natural
α-lipoic acid is R by the synthesis of its enantiomer [(S)-(–)-α-lipoic acid] from (S)-malic acid. J. Chem. Soc.
Chem. Commun. 1983, 19, 1051–1053. [CrossRef]
4. Ghibu, S.; Richard, C.; Vergely, C.; Zeller, M.; Cottin, Y.; Rochette, L. Antioxidant properties of an endogenous
thiol: Alpha-lipoic acid, useful in the prevention of cardiovascular diseases. J. Cardiovasc. Pharmacol. 2009,
54, 391–398. [CrossRef] [PubMed]
5. Brufani, M. Acido α-lipoico farmaco o integratore. Una panoramica sulla farmacocinetica, le formulazioni
disponibili e le evidenze cliniche nelle complicanze del diabete. Prog. Nutr. 2014, 16, 62–74.
6. Singh, U.; Jialal, I. Retracted: Alpha-lipoic acid supplementation and diabetes. Nutr. Rev. 2008, 66, 646–657.
[CrossRef] [PubMed]
7. Maglione, E.; Marrese, C.; Migliaro, E.; Marcuccio, F.; Panico, C.; Salvati, C.; Citro, G.; Quercio, M.;
Roncagliolo, F.; Torello, C.; et al. Increasing bioavailability of (R)-alpha-lipoic acid to boost antioxidant
activity in the treatment of neuropathic pain. Acta Bio-Medica Atenei Parm. 2015, 86, 226–233.
8. Packer, L.; Cadenas, E. Lipoic acid: Energy metabolism and redox regulation of transcription and cell
signaling. J. Clin. Biochem. Nutr. 2010, 48, 26–32. [CrossRef] [PubMed]
9. Konrad, D.; Somwar, R.; Sweeney, G.; Yaworsky, K.; Hayashi, M.; Ramlal, T.; Klip, A. The antihyperglycemic
drug alpha-lipoic acid stimulates glucose uptake via both GLUT4 translocation and GLUT4 activation:
Potential role of p38 mitogen-activated protein kinase in GLUT4 activation. Diabetes 2001, 50, 1464–1471.
[CrossRef] [PubMed]
10. Chen, W.-L.; Kang, C.-H.; Wang, S.-G.; Lee, H.-M. α-Lipoic acid regulates lipid metabolism through induction
of sirtuin 1 (SIRT1) and activation of AMP-activated protein kinase. Diabetologia 2012, 55, 1824–1835.
11. Gor ̨aca, A.; Huk-Kolega, H.; Piechota, A.; Kleniewska, P.; Ciejka, E.; Skibska, B. Lipoic acid–biological activity
and therapeutic potential. Pharmacol. Rep. 2011, 63, 849–858. [CrossRef]
12. Han, D.; Handelman, G.; Marcocci, L.; Sen, C.K.; Roy, S.; Kobuchi, H.; Tritschler, H.J.; Flohé, L.; Packer, L.
Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors
1997, 6, 321–338. [CrossRef] [PubMed]
13. Shay, K.P.; Moreau, R.F.; Smith, E.J.; Smith, A.R.; Hagen, T.M. Alpha-lipoic acid as a dietary supplement:
Molecular mechanisms and therapeutic potential. Biochim. Biophys. Acta 2009, 1790, 1149–1160. [CrossRef]
14. Ou, P.; Tritschler, H.J.; Wolff, S.P. Thioctic (lipoic) acid: A therapeutic metal-chelating antioxidant?
Biochem. Pharmacol. 1995, 50, 123–126. [CrossRef]
15. Bilska, A.; Wlodek, L. Lipoic acid-the drug of the future. Pharmacol. Rep. 2005, 57, 570–577.
16. Castro, M.C.; Villagarcía, H.G.; Massa, M.L.; Francini, F. Alpha-lipoic acid and its protective role in fructose
induced endocrine-metabolic disturbances. Food Funct. 2019, 10, 16–25. [CrossRef] [PubMed]
17. Keith, D.J.; Butler, J.A.; Bemer, B.; Dixon, B.; Johnson, S.; Garrard, M.; Sudakin, D.L.; Christensen, J.M.;
Pereira, C.; Hagen, T.M. Age and gender dependent bioavailability of R- and R,S-alpha-lipoic acid: A pilot
study. Pharmacol. Res. 2012, 66, 199–206. [CrossRef]
18. Packer, L.; Witt, E.H.; Tritschler, H.J. alpha-Lipoic acid as a biological antioxidant. Free Radic. Boil. Med. 1995,
19, 227–250. [CrossRef]
19. Carreau, J.-P. [32] Biosynthesis of lipoic acid via unsaturated fatty acids. Meth. Enzymol. 1979, 62, 152–158.
20. Ziegler, D. Thioctic acid for patients with symptomatic diabetic polyneuropathy: A critical review.
Treat Endocrino 2004, 3, 173–179. [CrossRef]
21. Henriksen, E.J. Exercise training and the antioxidant alpha-lipoic acid in the treatment of insulin resistance
and type 2 diabetes. Free Radic. Boil. Med. 2006, 40, 3–12. [CrossRef] [PubMed]
22. Ciftci, H.; Bakal, U. The effect of lipoic acid on macro and trace metal levels in living tissues exposed to
oxidative stress. Anti-Cancer Agents Med. Chem. 2009, 9, 560–568. [CrossRef]

Biomolecules 2019, 9, 356 20 of 25
23. Golbidi, S.; Badran, M.; Laher, I. Diabetes and alpha lipoic acid. Front. Pharmacol. 2011, 2, 69. [CrossRef]
24. Szel ̨ag, M.; Mikulski, D.; Molski, M. Quantum-chemical investigation of the structure and the antioxidant
properties of α-lipoic acid and its metabolites. J. Mol. Modeling 2012, 18, 2907–2916. [CrossRef] [PubMed]
25. Akiba, S.; Matsugo, S.; Packer, L.; Konishi, T. Assay of protein-bound lipoic acid in tissues by a new enzymatic
method. Anal. Biochem. 1998, 258, 299–304. [CrossRef] [PubMed]
26. Moura, F.A.; de Andrade, K.Q.; dos Santos, J.C.; Goulart, M.O. Lipoic acid: Its antioxidant and
anti-inflammatory role and clinical applications. Curr. Topics Med. Chem. 2015, 15, 458–483.
27. Gomes, M.B.; Negrato, C.A. Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in
diabetes and other chronic diseases. Diabetol. Metab. Syndr. 2014, 6, 80. [CrossRef]
28. Smith, A.R.; Shenvi, S.V.; Widlansky, M.; Suh, J.H.; Hagen, T.M. Lipoic acid as a potential therapy for chronic
diseases associated with oxidative stress. Curr. Med. Chem. 2004, 11, 1135–1146. [CrossRef]
29. Liu, J.; Head, E.; Gharib, A.M.; Yuan, W.; Ingersoll, R.T.; Hagen, T.M.; Cotman, C.W.; Ames, B.N. Memory
loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: Partial reversal by
feeding acetyl-L-carnitine and/or R-α-lipoic acid. Proc. Natl. Acad. Sci. USA 2002, 99, 2356–2361. [CrossRef]
30. Han, D.; Sen, C.K.; Roy, S.; Kobayashi, M.S.; Tritschler, H.J.; Packer, L. Protection against glutamate-induced
cytotoxicity in C6 glial cells by thiol antioxidants. Am. J. Physiol. Integr. Comp. Physiol. 1997, 273, 1771–1778.
31. Wray, D.W.; Nishiyama, S.K.; Harris, R.A.; Zhao, J.; McDaniel, J.; Fjeldstad, A.S.; Richardson, R.S. Acute
reversal of endothelial dysfunction in the elderly after antioxidant consumption. Hypertension 2012, 59,
818–824. [CrossRef] [PubMed]
32. McNeilly, A.M.; Davison, G.W.; Murphy, M.H.; Nadeem, N.; Trinick, T.; Duly, E.; McEneny, J. Effect of
α-lipoic acid and exercise training on cardiovascular disease risk in obesity with impaired glucose tolerance.
Lipids Heal. Dis. 2011, 10, 217. [CrossRef] [PubMed]
33. Ying, Z.; Kherada, N.; Farrar, B.; Kampfrath, T.; Chung, Y.; Simonetti, O.; Deiuliis, J.; Desikan, R.; Khan, B.;
Villamena, F.; et al. Lipoic acid effects on established atherosclerosis. Life Sci. 2010, 86, 95–102. [CrossRef]
34. Park, S.; Karunakaran, U.; Jeoung, N.H.; Jeon, J.-H.; Lee, I.-K. Physiological effect and therapeutic application
of alpha lipoic acid. Curr. Med. Chem. 2014, 21, 3636–3645. [CrossRef] [PubMed]
35. El Barky, A.R.; Hussein, S.A.; Mohamed, T.M. The potent antioxidant alpha lipoic acid. J. Plant Chem.
Ecophysiol. 2017, 2, 1016.
36. Biewenga, G.P.; Haenen, G.R.; Bast, A. The pharmacology of the antioxidant lipoic acid. Gen. Pharmacol.
Vasc. Syst. 1997, 29, 315–331. [CrossRef]
37. Goralska, M.; Dackor, R.; Holley, B.; McGahan, M.C. Alpha lipoic acid changes iron uptake and storage in
lens epithelial cells. Exp. Eye Res. 2003, 76, 241–248. [CrossRef]
38. Suzuki, Y.J.; Tsuchiya, M.; Packer, L. Thioctic acid and dihydrolipoic acid are novel antioxidants which
interact with reactive oxygen species. Free Radic. Res. Commun. 1991, 15, 255–263. [CrossRef]
39. Scott, B.C.; Aruoma, O.I.; Evans, P.J.; O’Neill, C.; Van der Vliet, A.; Cross, C.E.; Tritschler, H.; Halliwell, B.
Lipoic and dihydrolipoic acids as antioxidants. A critical evaluation. Free Radic. Res. 1994, 20, 119–133.
40. Islam, M.T. Antioxidant activities of dithiol alpha-lipoic acid. Bangladesh J. Med. Sci. 2009, 8, 34–49. [CrossRef]
41. WHO. Diabetes; World Health Organization: Geneva, Switzerland, 2018.
42. Moodley, K.; Joseph, K.; Naidoo, Y.; Islam, S.; Mackraj, I. Antioxidant, antidiabetic and hypolipidemic effects
of Tulbaghia violacea Harv. (wild garlic) rhizome methanolic extract in a diabetic rat model. BMC Complement.
Altern. Med. 2015, 15, 408. [CrossRef] [PubMed]
43. Beckman, J.A.; Creager, M.A.; Libby, P. Diabetes and atherosclerosis: Epidemiology, pathophysiology, and
management. J. Am. Med. Assoc. 2002, 287, 2570–2581. [CrossRef] [PubMed]
44. Giacco, F.; Brownlee, M. Oxidative stress and diabetic complications. Circ. Res. 2010, 107, 1058–1070.
[CrossRef] [PubMed]
45. Pitocco, D.; Tesauro, M.; Alessandro, R.; Ghirlanda, G.; Cardillo, C. Oxidative Stress in Diabetes: Implications
for Vascular and Other Complications. Int. J. Mol. Sci. 2013, 14, 21525–21550. [CrossRef] [PubMed]
46. Asmat, U.; Abad, K.; Ismail, K. Diabetes mellitus and oxidative stress-A concise review. Saudi Pharm. J. 2016,
24, 547–553. [CrossRef] [PubMed]

Biomolecules 2019, 9, 356 21 of 25
47. Eason, R.C.; Archer, H.E.; Akhtar, S.; Bailey, C.J. Lipoic acid increases glucose uptake by skeletal muscles of
obesediabetic ob/ob mice. Diabetes Obes. Metab. 2002, 4, 29–35. [CrossRef] [PubMed]
48. García-Osta, A.; Cuadrado-Tejedor, M.; García-Barroso, C.; Oyarzábal, J.; Franco, R. Phosphodiesterases as
therapeutic targets for Alzheimer’s disease. ACS Chem. Neurosci. 2012, 3, 832–844. [CrossRef]
49. Wu, Y.; Li, Z.; Huang, Y.Y.; Wu, D.; Luo, H.B. Novel phosphodiesterase inhibitors for cognitive improvement
in Alzheimer’s disease. J. Med. Chem. 2018, 61, 5467–5483. [CrossRef] [PubMed]
50. Perry, G.; Cash, A.D.; Smith, M.A. Alzheimer disease and oxidative stress. J. Biomed. Biotechnol. 2002, 2,
120–123. [CrossRef]
51. Chen, Z.; Zhong, C. Oxidative stress in Alzheimer’s disease. Neurosci. Bull. 2014, 30, 271–281. [CrossRef]
52. Huang, W.-J.; Zhang, X.; Chen, W.-W. Role of oxidative stress in Alzheimer’s disease. Biomed. Rep. 2016, 4,
519–522. [CrossRef]
53. Cacciatore, I.; Marinelli, L.; Fornasari, E.; Cerasa, L.S.; Eusepi, P.; Türkez, H.; Pomilio, C.; Reale, M.;
D’Angelo, C.; Costantini, E.; et al. Novel NSAID-derived drugs for the potential treatment of Alzheimer’s
disease. Int. J. Mol. Sci. 2016, 17, 1035. [CrossRef] [PubMed]
54. Hagen, T.M.; Ingersoll, R.T.; Lykkesfeldt, J.; Liu, J.; Wehr, C.M.; Vinarsky, V.; Bartholomew, J.C.; Ames, A.B.
(R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative
damage, and increased metabolic rate. FASEB J. 1999, 13, 411–418. [CrossRef] [PubMed]
55. Farr, S.A.; Poon, H.F.; Dogrukol-Ak, D.; Drake, J.; Banks, W.A.; Eyerman, E.; Allan Butterfield, D.; Morley, J.E.
The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative
stress in aged SAMP8 mice. J. Neurochem. 2003, 84, 1173–1183. [CrossRef] [PubMed]
56. Ono, K.; Hirohata, M.; Yamada, M. α-Lipoic acid exhibits anti-amyloidogenicity for β-amyloid fibrils in vitro.
Biochem. Biophys. Res. Commun. 2006, 341, 1046–1052. [CrossRef] [PubMed]
57. Zhang, W.-J.; Frei, B. Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion
molecule expression in human aortic endothelial cells. FASEB J. 2001, 15, 2423–2432. [CrossRef] [PubMed]
58. Lovell, M.A.; Xie, C.; Xiong, S.; Markesbery, W. Protection against amyloid beta peptide and iron/hydrogen
peroxide toxicity by alpha lipoic acid. J. Alzheimer’s Dis. 2003, 5, 229–239. [CrossRef]
59. Holmquist, L.; Stauchbury, G.; Berbaum, K.; Muscat, S.; Young, S.; Hager, K.; Engel, J.; Münch, G. Lipoic
acid as a novel treatment for Alzheimer’s disease and related demenias. Pharmacol. Ther. 2007, 113, 154–164.
60. Haugaard, N.; Levin, R.M. Regulation of the activity of choline acetyl transferase by lipoic acid.
Mol. Cell. Biochem. 2000, 213, 61–63. [CrossRef]
61. Meraz-Ríos,M.A.; Toral-Rios, D.; Franco-Bocanegra, D.; Villeda-Hernández, J.; Campos-Peña, V. Inflammatory
process in Alzheimer’s disease. Front. Integr. Neurosci. 2013, 7, 59. [CrossRef]
62. Ooi, L.; Patel, M.; Münch, G. The thiol antioxidant lipoic acid and Alzheimer’s disease. In Systems Biology of
Free Radicals and Antioxidants; Laher, I., Ed.; Springer: Berlin/Heidelberg, Germany, 2014; pp. 2275–2288.
63. Suh, J.H.; Wang, H.; Liu, R.-M.; Liu, J.K.; Hagena, T.M. (R)-α-Lipoic acid reverses the age-related loss in
GSH redox status in post-mitotic tissues: Evidence for increased cysteine requirement for zGSH synthesis.
Arch. Biochem. Biophys. 2015, 423, 126–135. [CrossRef] [PubMed]
64. Hardas, S.S.; Sultana, R.; Clark, A.M.; Beckett, T.L.; Szweda, L.I.; Murphy, P.; Butterfielda, D.A. Oxidative
modification of lipoic acid by HNE in Alzheimer disease brain. Redox Biol. 2013, 1, 80–85. [CrossRef]
65. Breitzig, M.; Bhimineni, C.; Lockey, R.; Kolliputi, N. 4-Hydroxy-2-nonenal: A critical target in oxidative
stress? Am. J. Physiol. Cell Physiol. 2016, 311, 537–543. [CrossRef] [PubMed]
66. Wong, A.; Dukic-Stefanovic, S.; Gasic-Milenkovic, J.; Schinzel, R.; Wiesinger, H.; Riederer, P.; Münch, G.
Anti-inflammatory antioxidants attenuate the expression of inducible nitric oxide synthase mediated by
advanced glycation endproducts in murine microglia. Eur. J. Neurosci. 2001, 14, 1961–1967. [CrossRef]
67. Dinicola, S.; Proietti, S.; Cucina, A.; Bizzarri, M.; Fuso, A.J.A. Alpha-Lipoic Acid Downregulates IL-1β
and IL-6 by DNA Hypermethylation in SK-N-BE Neuroblastoma Cells. Antioxidant 2017, 6, 74. [CrossRef]
68. Schwartz, L.; Abolhassani, M.; Guais, A.; Sanders, E.; Steyaert, J.M.; Campion, F.; Israël, M. A combination of
alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: Preliminary results.
Oncol. Rep. 2010, 23, 1407–1420. [CrossRef]

Biomolecules 2019, 9, 356 22 of 25
69. Na, M.H.; Seo, E.Y.; Kim, W.K. Effects of alpha-lipoic acid on cell proliferation and apoptosis in MDA-MB-231
human breast cells. Nutr. Res. Pract. 2009, 3, 265–271. [CrossRef]
70. Ganapathy-Kanniappan, S.; Geschwind, J.F. Tumor glycolysis as a target for cancer therapy: Progress and
prospects. Mol. Cancer 2013, 12, 152. [CrossRef]
71. Zhang, C.; Liu, J.; Liang, Y.; Wu, R.; Zhao, Y.; Hong, X.; Lin, M.; Yu, H.; Liu, L.; Levine, A.J.; et al.
Tumour-associated mutant p53 drives the Warburg effect. Nat. Commun. 2013, 4, 2935. [CrossRef]
72. Feuerecker, B.; Pirsig, S.; Seidl, C.; Aichler, M.; Feuchtinger, A.; Bruchelt, G.; Senekowitsch-Schmidtke, R.
Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo. Cancer Biol. Ther. 2012, 13, 1425–1435.
73. Jeon, M.J.; Kim, W.G.; Lim, S.; Choi, H.J.; Sim, S.; Kim, T.Y.; Shong, Y.K.; Kim, W.B. Alpha lipoic acid inhibits
proliferation and epithelial mesenchymal transition of thyroid cancer cells. Mol. Cell. Endocrinol. 2016, 419,
113–123. [CrossRef] [PubMed]
74. Yang, L.; Wen, Y.; Lv, G.; Lin, Y.; Tang, J.; Lu, J.; Zhang, M.; Liu, W.; Sun, X. a-Lipoic acid inhibits human lung
cancer cell proliferation through Grb2-mediated EGFR down regulation. Biochem. Biophys. Res. Commun.
2017, 494, 325–331. [CrossRef] [PubMed]
75. Moungjaroen, J.; Nimmannit, U.; Callery, P.S.; Wang, L.; Azad, N.; Lipipun, V.; Chanvorachote, P.;
Rojanasakul, Y. Reactive oxygen species mediate caspase activation and apoptosis induced by lipoic
acid in human lung epithelial cancer cells through Bcl-2 down-regulation. J. Pharmacol. Exp. Ther. 2006, 319,
1062–1069. [CrossRef] [PubMed]
76. Dozio, E.; Ruscica, M.; Passafaro, L.; Dogliotti, G.; Steffani, L.; Marthyn, P.; Pagani, A.; Demartini, G.;
Esposti, D.; Fraschini, F.; et al. The natural antioxidant alpha-lipoic acid induces p27(Kip1)-dependent cell
cycle arrest and apoptosis in MCF-7 human breast cancer cells. Eur. J. Pharmacol. 2010, 641, 29–34. [CrossRef]
77. Wenzel, U.; Nickel, A.; Daniel, H. α-Lipoic acid induces apoptosis in human colon cancer cells by increasing
mitochondrial respiration with a concomitant O2-*-generation. Apoptosis 2005, 10, 359–368. [CrossRef]
78. Trivedi, P.P.; Jena, G.B. Role of α-lipoic acid in dextran sulfate sodium-induced ulcerative colitis in mice:
Studies on inflammation, oxidative stress, DNA damage and fibrosis. Food Chem. Toxicol. 2013, 59, 339–355.
79. Tripathy, J.; Tripathy, A.; Thangaraju, M.; Suar, M.; Elangovan, S. alpha-Lipoic acid inhibits the migration and
invasion of breast cancer cells through inhibition of TGFbeta signaling. Life Sci. 2018, 207, 15–22. [CrossRef]
80. Lee, W.J.; Song, K.H.; Koh, E.H.; Won, J.C.; Kim, H.S.; Park, H.S.; Kim, M.S.; Kim, S.W.; Lee, K.U.; Park, J.Y.
Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle. Biochem. Biophys.
Res. Commun. 2005, 332, 885–891. [CrossRef]
81. Bitar, M.S.; Ayed, A.K.; Abdel-Halim, S.M.; Isenovic, E.R.; Al-Mulla, F. Inflammation and apoptosis
in aortic tissues of aged type II diabetes: Amelioration with lipoic acid through phosphatidylinositol
3-kinase/Akt-dependent mechanism. Life Sci. 2010, 86, 844–853. [CrossRef]
82. Rochette, L.; Ghibu, S.; Muresan, A.; Vergely, C. Alpha-lipoic acid: Molecular mechanisms and therapeutic
potential in diabetes1. Can. J. Physiol. Pharmacol. 2015, 93, 1021–1027. [CrossRef]
83. Smith, A.R.; Hagen, T.M. Vascularendothelialdys- function inaging: Loss of Akt- dependent endothelial
nitricoxide synthase phosphorylation and partial restoration by (R)-alpha-lipoic acid. Biochem. Soc. Trans.
2003, 31, 1447–1449. [CrossRef] [PubMed]
84. Artwohl, M.; Muth, K.; Kosulin, K.; de Martin, R.; Holzenbein, T.; Rainer, G.; Freudenthaler, A.; Huttary, N.;
Schmetterer, L.; Waldhausl, W.K.; et al. R-(+)-alpha-lipoic acid inhibits endothelial cell apoptosis and
proliferation: Involvement of Akt and retinoblastoma protein/E2F-1. Am. J. Physiol. Endocrinol. Metab. 2007,
293, 681–689. [CrossRef] [PubMed]
85. Zhang, W.J.; Wei, H.; Hagen, T.; Frei, B. Alpha-lipoic acid attenuates LPS-induced inflammatory responses
by activating the phosphoinositide 3-kinase/Akt signaling pathway. Proc. Natl. Acad. Sci. USA 2007, 104,
4077–4082. [CrossRef] [PubMed]
86. Kawabata, T.; Packer, L. Alpha-lipoate can protect against glycation of serum albumin, but not low density
lipoprotein. Biochem. Biophys. Res. Commun. 1994, 203, 99–104. [CrossRef] [PubMed]
87. Thirunavukkarasu, V.; Nandhini, A.A.T.; Anuradha, C.V. Lipoic acid improves glucose utilisation and
prevents protein glycation and AGE formation. Die Pharm. 2005, 60, 772–775.

Biomolecules 2019, 9, 356 23 of 25
88. Quinn, J.F.; Bussiere, J.R.; Hammond, R.S.; Montine, T.J.; Henson, E.; Jones, R.E.; Stackman, R.W. Chronic
dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice. Neurobiol. Aging
2007, 28, 213–225. [CrossRef] [PubMed]
89. Suh, J.H.; Zhu, B.Z.; de Szoeke, E.; Frei, B.; Hagen, T.M. Dihydrolipoic acid lowers the redox activity of
transition metal ions but does not remove them from the active site of enzymes. Redox Rep. 2004, 9, 57–61.
[CrossRef] [PubMed]
90. Micili, S.C.; Goker, A.; Kuscu, K.; Ergur, B.U.; Fuso, A.J.R.S. α-Lipoic Acid Vaginal Administration Contrasts
Inflammation and Preterm Delivery in Rats. Reprod. Sci. 2019, 26, 128–138. [CrossRef] [PubMed]
91. Brufani, M.; Figliola, R. (R)-α-lipoic acid oral liquid formulation: Pharmacokinetic parameters and therapeutic
efficacy. Acta Bio-Medica Atenei Parm. 2014, 85, 108–115.
92. Gleiter, C.H.; Schug, B.S.; Hermann, R.; Elze, M.; Blume, H.H.; Gundert-Remy, U. Influence of food intake on
the bioavailability of thioctic acid enantiomers. Eur. J. Clin. Pharmacol. 1996, 50, 513–514. [CrossRef]
93. Hermann, R.; Niebch, G.; Borbe, H.O.; Fieger-Büschges, H.; Ruus, P.; Nowak, H.; Riethmüller-Winzen, H.;
Peukert, M.; Blume, H. Enantioselective pharmacokinetics and bioavailability of different racemic α-lipoic
acid formulations in healthy volunteers. Eur. J. Pharmacol. Sci. 1996, 4, 167–174. [CrossRef]
94. Teichert, J.; Tuemmers, T.; Achenbach, H.; Preiss, C.; Hermann, R.; Ruus, P.; Preiss, R. Pharmacokinetics of
alpha-lipoic acid in subjects with severe kidney damage and end-stage renal disease. J. Clin. Pharmacol. 2005,
45, 313–328. [CrossRef] [PubMed]
95. Breithaupt-Grogler, K.; Niebch, G.; Schneider, E.; Erb, K.; Hermann, R.; Blume, H.H.; Schug, B.S.; Belz, G.G.
Dose-proportionality of oral thioctic acid–coincidence of assessments via pooled plasma and individual data.
Eur. J. Pharm. Sci. 1999, 8, 57–65. [CrossRef]
96. Uchida, R.; Iwamoto, K.; Nagayama, S.; Miyajima, A.; Okamoto, H.; Ikuta, N.; Fukumi, H.; Terao, K.; Hirota, T.
Effect of gamma-Cyclodextrin Inclusion Complex on the Absorption of R-alpha-Lipoic Acid in Rats. Int. J.
Mol. Sci. 2015, 16, 10105–10120. [CrossRef] [PubMed]
97. Uchida, R.; Okamoto, H.; Ikuta, N.; Terao, K.; Hirota, T. Enantioselective Pharmacokinetics of alpha-Lipoic
Acid in Rats. Int. J. Mol. Sci. 2015, 16, 22781–22794. [CrossRef] [PubMed]
98. Mignini, F.; Nasuti, C.; Gioventu, G.; Napolioni, V.; Martino, P.D. Human bioavailability and pharmacokinetic
profile of different formulations delivering alpha lipoic acid. Open Access Sci. Rep. 2012, 1, 418. [CrossRef]
99. Hermann, R.; Mungo, J.; Cnota, P.J.; Ziegler, D. Enantiomer-selective pharmacokinetics, oral bioavailability,
and sex effects of various alpha-lipoic acid dosage forms. Clin. Pharmacol. 2014, 6, 195–204. [CrossRef]
100. Reed, L.J. The chemistry and function of lipoic acid. Adv. Enzymol. Related Areas Mol. Biol. 1957, 18, 319–347.
101. Kim, N.W.; Song, Y.M.; Kim, E.; Cho, H.S.; Cheon, K.A.; Kim, S.J.; Park, J.Y. Adjunctive α-lipoic acid
reduces weight gain compared with placebo at 12 weeks in schizophrenic patients treated with atypical
antipsychotics: A double-blind randomized placebo-controlled study. Int. Clin. Psychopharmacol. 2016, 31,
265–274. [CrossRef]
102. Sun, H.; Yao, W.; Tang, Y.; Zhuang, W.; Wu, D.; Huang, S.; Sheng, H. Urinary exosomes as a novel biomarker
for evaluation of α-lipoic acid’s protective effect in early diabetic nephropathy. J. Clin. Lab. Anal. 2017, 31,
e22129. [CrossRef]
103. De Sousa, C.N.S.; da Silva Leite, C.M.G.; da Silva Medeiros, I.; Vasconcelos, L.C.; Cabral, L.M.;
Patrocínio, C.F.V.; Patrocínio, M.L.V.; Mouaffak, F.; Kebir, O.; Macedo, D.; et al. Alpha-lipoic acid in
the treatment of psychiatric and neurological disorders: A systematic review. Metab. Brain Dis. 2019, 34,
39–52. [CrossRef] [PubMed]
104. The Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk
of vascular disease: A collaborative meta-analysis of 102 prospective studies. Lancet 2010, 375, 2215–2222.
105. Fowler, M.J. Microvascular and macrovascular complications of diabetes. Clin. Diabetes 2008, 26, 77–82.
106. Vinik, A.; Casellini, C.; Nevoret, M.L. Diabetic Neuropathies. In South Dartmouth; Feingold, K.R., Anawalt, B.,
Boyce, A., Chrousos, G., Dungan, K., Grossman, A., Hershman, J.M., Kaltsas, G., Koch, C., Kopp, P., et al.,
Eds.;, Inc.: South Dartmouth, MA, USA, 2000.
107. Ziegler, D.; Low, P.A.; Freeman, R.; Tritschler, H.J.; Vinik, A.I. Predictors of improvement and progression of
diabetic polyneuropathy following treatment with α-lipoic acid for 4 years in the NATHAN 1 trial. J. Diabetes
Its Complicat. 2016, 30, 350–356. [CrossRef] [PubMed]

Biomolecules 2019, 9, 356 24 of 25
108. Garcia-Alcala, H.; Santos Vichido, C.I.; Islas Macedo, S.; Genestier-Tamborero, C.N.; Minutti-Palacios, M.;
Hirales Tamez, O.; Garcia, C.; Ziegler, D. Treatment with alpha-Lipoic Acid over 16 Weeks in Type 2
Diabetic Patients with Symptomatic Polyneuropathy Who Responded to Initial 4-Week High-Dose Loading.
J. Diabetes Res. 2015, 2015, 189857. [CrossRef]
109. Agathos, E.; Tentolouris, A.; Eleftheriadou, I.; Katsaouni, P.; Nemtzas, I.; Petrou, A.; Papanikolaou, C.;
Tentolouris, N. Effect of α-lipoic acid on symptoms and quality of life in patients with painful diabetic
neuropathy. J. Int. Med. Res. 2018, 46, 1779–1790. [CrossRef]
110. WHO. Obesity and Overweight; World Health Organization: Geneva, Switzerland, 2018.
111. Flegal, K.M.; Graubard, B.I.; Williamson, D.F.; Gail, M.H. Cause-specific excess deaths associated with
underweight, overweight, and obesity. JAMA 2007, 298, 2028–2037. [CrossRef]
112. Van Kruijsdijk, R.C.M.; Van Der Wall, E.; Visseren, F.L.J. Obesity and cancer: The role of dysfunctional
adipose tissue. Cancer Epidemiol. Biomarkers Prev. 2009, 18, 2569–2578. [CrossRef]
113. Escoté, X.; Félix-Soriano, E.; Gayoso, L.; Huerta, A.E.; Alvarado, M.A.; Ansorena, D.; Astiasarán, I.;
Martínez, J.A.; Moreno-Aliaga, M.J. Effects of EPA and lipoic acid supplementation on circulating FGF21
and the fatty acid profile in overweight/obese women following a hypocaloric diet. Food Funct. 2018, 9,
3028–3036. [CrossRef]
114. Huerta, A.E.; Navas-Carretero, S.; Prieto-Hontoria, P.L.; Martínez, J.A.; Moreno-Aliaga, M.J. Effects of α-lipoic
acid and eicosapentaenoic acid in overweight and obese women during weight loss. Obesity 2015, 23, 313–321.
115. Li, N.; Yan, W.; Hu, X.; Huang, Y.; Wang, F.; Zhang, W.; Wang, Q.; Wang, X.; Sun, K. Effects of oral α-lipoic
acid administration on body weight in overweight or obese subjects: A crossover randomized, double-blind,
placebo-controlled trial. Clin. Endocrinol. 2017, 86, 680–687. [CrossRef] [PubMed]
116. Hosseinpour-Arjmand, S.; Amirkhizi, F.; Ebrahimi-Mameghani, M. The effect of alpha-lipoic acid on
inflammatory markers and body composition in obese patients with non-alcoholic fatty liver disease: A
randomized, double-blind, placebo-controlled trial. J. Clin. Pharm. Ther. 2019, 44, 258–267. [CrossRef]
117. Romo-Hualde, A.; Huerta, A.E.; González-Navarro, C.J.; Ramos-López, O.; Moreno-Aliaga, M.J.; Martínez, J.A.
Untargeted metabolomic on urine samples after α-lipoic acid and/or eicosapentaenoic acid supplementation
in healthy overweight/obese women. Lipids Health Dis. 2018, 17, 103. [CrossRef] [PubMed]
118. The American Psychiatric Association. Diagnostic and statistical manual of mental disorders; The American
Psychiatric Association: Washington, DC, USA, 2013.
119. Gold, J.M. Cognitive deficits as treatment targets in schizophrenia. Schizophr. Res. 2004, 72, 21–28. [CrossRef]
120. Friedman, J.I.; Wallenstein, S.; Moshier, E.; Parrella, M.; White, L.; Bowler, S.; Gottlieb, S.; Harvey, P.D.;
McGinn, T.G.; Flanagan, L. The effects of hypertension and body mass index on cognition in schizophrenia.
Am. J. Psychiatry 2010, 167, 1232–1239. [CrossRef] [PubMed]
121. Goughari, A.S.; Mazhari, S.; Pourrahimi, A.M.; Sadeghi, M.M.; Nakhaee, N. Associations between components
of metabolic syndrome and cognition in patients with schizophrenia. J. Psychiatr. Pract. 2015, 21, 190–197.
[CrossRef] [PubMed]
122. Sanders, L.L.O.; de Souza Menezes, C.E.; Chaves Filho, A.J.M.; de Almeida Viana, G.; Fechine, F.V.;
de Queiroz, M.G.R.; da Cruz Fonseca, S.G.; Vasconcelos, S.M.M.; de Moraes, M.E.A.; Gama, C.S. α-Lipoic acid
as adjunctive treatment for Schizophrenia: An open-label trial. J. Clin. Psychopharmacol. 2017, 37, 697–701.
[CrossRef] [PubMed]
123. Vidovi ́c, B.; Milovanovi ́c, S.; Stefanovi ́c, A.; Kotur-Stevuljevi ́c, J.; Taki ́c, M.; Debeljak-Martaˇci ́c, J.; Pantovi ́c, M.;
Đorđevi ́c, B. Effects of alpha-lipoic acid supplementation on plasma adiponectin levels and some metabolic
risk factors in patients with schizophrenia. J. Med. Food 2017, 20, 79–85. [CrossRef]
124. Confavreux, C.; Vukusic, S.; Moreau, T.; Adeleine, P. Relapses and progression of disability in multiple
sclerosis. N. Engl. J. Med. 2000, 343, 1430–1438. [CrossRef]
125. Marracci, G.H.; Jones, R.E.; McKeon, G.P.; Bourdette, D.N. Alpha lipoic acid inhibits T cell migration into the
spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. J. Neuroimmunol. 2002,
131, 104–114. [CrossRef]

Biomolecules 2019, 9, 356 25 of 25
126. Yadav, V.; Marracci, G.; Lovera, J.; Woodward, W.; Bogardus, K.; Marquardt, W.; Shinto, L.; Morris, C.;
Bourdette, D. Lipoic acid in multiple sclerosis: A pilot study. Mult. Scler. J. 2005, 11, 159–165. [CrossRef]
127. Dutta, R.; Trapp, B.D. Relapsing and progressive forms of multiple sclerosis–insights from pathology.
Curr. Opin. Neurol. 2014, 27, 271–278. [CrossRef] [PubMed]
128. Khalili, M.; Azimi, A.; Izadi, V.; Eghtesadi, S.; Mirshafiey, A.; Sahraian, M.A.; Motevalian, A.; Norouzi, A.;
Sanoobar, M.; Eskandari, G.; et al. Does lipoic acid consumption affect the cytokine profile in multiple
sclerosis patients: A double-blind, placebo-controlled, randomized clinical trial. Neuroimmunomodulation
2014, 21, 291–296. [CrossRef] [PubMed]
129. Loy, B.D.; Fling, B.W.; Horak, F.B.; Bourdette, D.N.; Spain, R.I. Effects of lipoic acid on walking performance,
gait, and balance in secondary progressive multiple sclerosis. Complement. Ther. Med. 2018, 41, 169–174.
[CrossRef] [PubMed]
130. Fiedler, S.E.; Yadav, V.; Kerns, A.R.; Tsang, C.; Markwardt, S.; Kim, E.; Spain, R.; Bourdette, D.; Salinthone, S.
Lipoic acid stimulates cAMP production in healthy control and secondary progressive MS subjects.
Mol. Neurobiol. 2018, 55, 6037–6049. [CrossRef] [PubMed]
131. Yamada, T.; Atsuki, Y.; Wakasaya, A.; Kobayashi, M.; Hirano, Y.; Ohwada, M. Characteristics of patients
with subchorionic hematomas in the second trimester. J. Obstet. Gynaecol. Res. 2012, 38, 180–184. [CrossRef]
132. ̧Sükür, Y.E.; Göç, G.; Köse, O.; Açmaz, G.; Özmen, B.; Atabeko ̆glu, C.S.; Koç, A.; Söylemez, F. The effects
of subchorionic hematoma on pregnancy outcome in patients with threatened abortion. J. Turkish German
Gynecol. Assoc. 2014, 15, 239. [CrossRef] [PubMed]
133. Carp, H.J.A. Progestogens and pregnancy loss. Climacteric 2018, 21, 380–384. [CrossRef]
134. Porcaro, G.; Brillo, E.; Giardina, I.; Di Iorio, R. Alpha Lipoic Acid (ALA) effects on subchorionic hematoma:
Preliminary clinical results. Eur. Rev. Med. Pharmacol. Sci. 2015, 19, 3426–3432.
135. Grandi, G.; Pignatti, L.; Ferrari, F.; Dante, G.; Neri, I.; Facchinetti, F. Vaginal alpha-lipoic acid shows an
anti-inflammatory effect on the cervix, preventing its shortening after primary tocolysis. A pilot, randomized,
placebo-controlled study. J. Matern. Fetal Neonatal Med. 2017, 30, 2243–2249. [CrossRef]
136. Costantino, M.; Guaraldi, C.; Costantino, D. Resolution of subchorionic hematoma and symptoms of
threatened miscarriage using vaginal alpha lipoic acid or progesterone: Clinical evidences. Eur. Rev. Med.
Pharmacol. Sci. 2016, 20, 1656–1663. [PubMed]
137. Ambrosi, N.; Arrosagaray, V.; Guerrieri, D.; Uva, P.D.; Petroni, J.; Herrera, M.B.; Iovanna, J.L.; Leon, L.;
Incardona, C.; Chuluyan, H.E.; et al. alpha-Lipoic acid protects against ischemia-reperfusion injury in
simultaneous kidney-pancreas transplantation. Transplantation 2016, 100, 908–915. [CrossRef] [PubMed]
138. Casciato, P.; Ambrosi, N.; Caro, F.; Vazquez, M.; Müllen, E.; Gadano, A.; de Santibañes, E.; de Santibañes, M.;
Zandomeni, M.; Chahdi, M. α-Lipoic acid reduces postreperfusion syndrome in human liver transplantation-a
pilot study. Transpl. Int. 2018, 31, 1357–1368. [CrossRef] [PubMed]
139. Guo, Y.; Jones, D.; Palmer, J.L.; Forman, A.; Dakhil, S.R.; Velasco, M.R.; Weiss, M.; Gilman, P.; Mills, G.M.;
Noga, S.J.; et al. Oral alpha-lipoic acid to prevent chemotherapy-induced peripheral neuropathy: A
randomized, double-blind, placebo-controlled trial. Support. Care Cancer 2014, 22, 1223–1231. [CrossRef]

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (

Leave a reply