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Alpha-Lipoic Acid
Antiviral, Antioxidant for HIV and Liver Disease
(Special thanks to Mark Kuebel for his invaluable help in researching
and writing this Information Sheet)
What Is It?
Alpha-lipoic acid, also commonly called Thioctic acid, is fast
becoming recognized as another treatment for HIV disease which plays
several roles and addresses different problems. It is a small,
sulfur-containing molecule that easily passes into cells from the
bloodstream and is both water and fat soluble. Thioctic acid is
produced in extremely small quantities by cells, where it acts as a
coenzyme in production of energy molecules (known as ATP) from food. A
coenzyme is a substance that activates enzymes; the enzymes then help
to speed up reactions between other molecules. When supplemented,
thioctic acid is also a very powerful antioxidant outside of its
normal role in energy production.
The existence of alpha-lipoic acid was first suspected in
1937--researchers recognized that some as yet unidentified chemical
was involved in certain chemical reactions and was characterized in
1957. It is an integral coenzyme of mitochondrial production of ATP
from glucose, water and oxygen as part of the Kreb's (citric acid)
cycle. It naturally occurs tightly bound within mitochondria and is
not typically found in the cell fluid (cytoplasm) or other cellular
organelles (e.g., the nucleus). Supplementation increases its
availability for other cell parts, like inside the nucleus or in the
main part of the cytoplasm.
The alpha-lipoic acid molecule itself is a single-chain fatty acid
based on octanoic (or caprylic) acid--one of the constituents of
butter fat, for example, when the molecules are separated
(hydrolyzed). Lipoic acid is different from octanoic acid by virtue of
the sulfur atoms it has. It is the disulfide of two dihydrolipoate
molecules connected together at the sulfur bridge (like cystine is two
cysteines connected together). Because it is a small molecule, it
passes easily through biological membranes and is soluble in both
aqueous (water) and lipid (fat) environments. It gets into just about
all tissues, including the brain. This allows alpha-lipoic acid to
penetrate the nuclear envelope as well as the cytoplasm. Thus, it
operates within a cell's nucleus, in cytoplasm and can be found in
blood and in interstitial spaces (in the spaces within organs or
tissues) (Passwater, 1995).
Are There Deficiencies in HIV Infection?
Alpha-lipoic acid is not known to be deficient in HIV disease.
However, studies have yet to determine this. Naturally occurring
alpha-lipoic acid exists in energy-producing cell structures called
mitochondria, where it remains tightly bound. Mitochondria float
around in cells and change sugar into ATP, which is the most common
energy molecule of cells. Alpha-lipoic acid is used by enzymes in this
energy-production system in minute quantities, along with carnitine,
coenzyme Q10 and other players. The mechanism for alpha-lipoic acid
production in cells has yet to be fully explained, and all
alpha-lipoic acid produced for supplementation is made synthetically.
It should be noted that one type of damage done by AZT is to cellular
mitochondria.
Studies (Laboratory, Animal, Human)
Alpha-lipoic acid's primary feature--separating it from other
antioxidants--is its exceptional ability to act as a reducing agent.
This means it more readily donates electrons to molecules with a net
positive charge than many antioxidants and is easily recycled back to
its reduced state by intracellular glutathione reductase. The main
task of this enzyme is to transform oxidized glutathione (GSSG) back
to the active reduced form, GSH. This recycling mechanism is not
nearly as efficient in recycling alpha-lipoic acid, but it
significantly adds to the appeal of using it as a treatment for
oxidative stress (Passwater, 1995).
Through this antioxidant action, alpha-lipoic acid helps to keep
NF-kB, a cellular protein which activates HIV expression (see below).
Other features of alpha-lipoic acid important to PWAs are its ability
to aid in the recycling of vitamins C and E; its ability to replace
lost glutathione in intracellular free radical defense; and its
ability to reduce or eliminate plaque formation (clumping) of CD4
lymphocytes (syncytia), which is a suspected mechanism in the killing
of uninfected T cells (Passwater, 1995; Suzuki, 1994; Suzuki, 1992).
When alpha-lipoic acid (which is considered its oxidized state) enters
a typical cell, most of it is reduced to dihydrolipoic acid, which has
greater potential than alpha-lipoic acid to neutralize reactive oxygen
species. Dihydrolipoic acid has the same backbone structure as
alpha-lipoic acid, except its disulfide connection is broken (Bast,
1990). Another metabolic product that comes from alpha-lipoic acid is
tetranorlipoic acid, which has been shown to be very potent for
inhibition of NF-kB (Suzuki, 1994). Through Suzuki and Packer's work,
it is evident that two portions of this molecule are active in
inhibiting NF-kB, including the hydrocarbon backbone and the cyclic
disulfide side chain. The cyclic disulfide/dual SH- moieties (parts)
are much more potent than the hydrocarbon chain. (The sulfhydryl group
[SH] donates two hydrogen ions [protons denoted H-] to reduce oxidant
molecules. Again, because repetition is good for the soul, the
dihydrolipoate is oxidized, and a disulfide bridge forms between the
two sulfur atoms to form the cyclic compound alpha-lipoic acid.)
Alpha-lipoic acid has also been shown to aid in the recycling of
reduced vitamin C and, thereby, vitamin E. Alpha-lipoic acid reduces
dehydroascorbate (oxidized ascorbate) back to vitamin C, which in turn
reduces vitamin E. This maintains a steady state of both vitamins C
and E (Kagan, 1992; Passwater, 1995). When Kagan's group added
dihydrolipoate acid to a mixture of plasma lipoproteins (a fat-protein
mixture that mimics a cell's membrane) undergoing peroxidation
(oxidative stress), the ability of ascorbate to recycle vitamin E
increased greatly. Thus there was more vitamin E available in a form
that was effective in limiting the damage to cellular membranes
induced by the oxidative stress. This effect was shown in other test
situations with liposomes (balls of fat), microsomes (balls composed
of a cellular organ, the endoplasmic reticulum), membranes and tissue
homogenates (blended tissues) (Kagan, 1991).
The role of glutathione as the primary cellular antioxidant, and its
often extreme deficiency in people with HIV, cannot be overemphasized
when discussing the use of antioxidant therapy for HIV/AIDS. (Please
see the Glutathione Information Sheet). Alpha-lipoic acid has the
ability to recycle oxidized glutathione (GSSG) back to reduced
glutathione (GSH), possibly by simply donating electrons to GSSG
(although the mechanism is not clear). Alpha-lipoic acid in turn, is
then reduced by glutathione reductase and other enzymes. Because
intracellular alpha-lipoic acid concentrations are in the range of
nanomoles (nM, extremely low concentration) and glutathione is in the
range of millimoles (mM, which is relatively high), the recycling of
alpha-lipoic acid takes place without interfering with the recycling
of GSSG to GSH (Kis, 1996).
In fact, the concentration of glutathione in the cytoplasm is among
the highest of any substance in healthy tissues and alpha lipoic acid
can improve this level. A pilot study in people with AIDS (CDC stage
IV) has confirmed the in vitro studies of alpha-lipoic acid's
abilities to recycle cellular antioxidants and vitamins with 100%
response rate for increased total glutathione (7 of 7 patients).
Increases in vitamin C were also noted in 9 of 10, while a decrease in
markers of lipid peroxidation was shown in most patients (7 of 9 for
the marker, 4-hydroxynonenal and in 8 of 9 for malondialdehyde). CD4
counts and CD4/CD8 ratios were improved in 6 of 10 (Fuchs, 1993).
The increase of cellular GSH in T-lymphocyte Jurkat cells is induced
by an increase in lipoate concentration and is not dependent on the
synthesis of enzymes that may synthesize glutathione. It appears to be
a direct effect of lipoic acid (as dihydrolipoic acid) on GSSG (Han,
1995; Passwater, 1995). Because GSH protects against lipid
peroxidation and plays a "pivotal role" in maintaining membrane
integrity both inside cells and the plasma membrane itself (Bast,
1990), any drop in GSH levels may effect physiological exchanges that
take place across lipid membranes, like the absorption of nutrients
from blood, oxygenation of cytoplasm, and a myriad of other processes.
(Please review the Information Sheet on Glutathione.)
A test tube study compared the effects of fat-soluble antioxidants
(e.g., vitamin E) to water-soluble antioxidants (like alpha-lipoic
acid) to determine their effect on the amount of HIV produced by
monocytes. Such studies traditionally have used concentrations that
are beyond what can be obtained physiologically--that is, you'd have
to wolf down huge quantities to have any effect. When they used a more
reasonable concentration, they found a small inhibition--a 30%
reduction in expression. However, when they mixed the water-soluble
and fat-soluble vitamins together, they saw a much more substantial
inhibition of 50 to 80% (Saliou, 1996). Another study is being
conducted in the United States to determine if there is efficacy in
treating HIV-related dementia (protocol number FDA 250A) and plans are
being discussed at AmFAR for a (more sensible?) approach of using a
combination to improve liver function.
How Does It Work and How Does It Work in HIV Infection?
Because it can pass into cells easily, alpha-lipoic acid acts as an
antioxidant in all parts of cells and tissues, thereby slowing the
damaging effects of HIV and other oxidant-generating toxins, viruses
and bacteria. But most importantly, it can slow the multiplication of
HIV. Many antioxidants do their primary work in the bloodstream, but
alpha-lipoic acid has the ability to penetrate all areas of cells,
meaning it can work in the cell's nucleus where HIV resides and
multiplies (Passwater, 1995). Thus, it gets into tissues that some
drugs do not reach.
Human cells do not use alpha-lipoic acid as a broad-spectrum
antioxidant; instead, they use the less powerful molecule glutathione.
Glutathione is a cell's most important naturally-occurring antioxidant
defense and is also chronically deficient in people with HIV. The
antioxidant properties of alpha-lipoic acid can be broadened to the
entire body when taken as a supplement, helping to make up for
HIV-caused deficiency of glutathione (Busse, 1992; Han, 1995).
Alpha-lipoic acid is an agent that reduces the oxidizing strength of
molecules. Therefore, it is able to "soothe" oxidant molecules that
cause inflammation and cell membrane damage throughout the body. This
effect neutralizes the oxidant molecules, keeping them from causing
their usual damage. Normally, this is done by glutathione, but
glutathione is deficient in PWHIV (Buhl, 1989; Droge, 1988; Eck, 1989;
Staal, 1992). Because much inflammation associated with HIV is caused
by oxidative stress, use of antioxidant supplements like vitamin C,
bioflavonoids, NAC, vitamin E, beta carotene, amino acids,
glycyrrhizin and others are an important strategy in reducing
degrading effects of HIV infection. Alpha-lipoic acid has now been
added to this list of antioxidants. Not only does it recycle the
important antioxidants glutathione, vitamin C and vitamin E, but it
also helps to turn off the pathway in HIV-infected cells that turns on
HIV multiplication (Passwater, 1995).
Because of its strong reducing properties, alpha-lipoic acid also
helps prevent the activation of HIV multiplication in HIV-infected
cells (Baur, 1991). The second function of alpha-lipoic acid in
stopping viral replication is a complicated process. In simple terms,
alpha-lipoic acid prevents an infected cell from turning on the genes
of HIV in the cell nucleus. The insidious nature of HIV is such that
it incorporates itself into the genes of HIV-infected cells, actually
becoming part of a human gene. Genes need triggers from the cell to
turn on the production of new proteins from the genetic code. A
special molecular complex called nuclear factor kappa B (NF-kB) is the
complex that turns on HIV genes (and other genes) in an infected
cell's nucleus. Oxidants in the cell not scavenged by glutathione
activate the NF-kB to turn on HIV multiplication. Alpha-lipoic acid
prevents this by keeping oxidants cleaned up inside the cell, thereby
keeping NF-kB from being stimulated (Suzuki, 1992). Thus, HIV remains
dormant in the genes, oxidants are neutralized, and the cell remains
alive and healthy. (See the Immunology Primer and the first sections
of the DAAIR TIP.)
NF-kB is a gene activator protein that resides in a cell's cytoplasm.
Free radical damage in a cell will often trigger the transformation of
NF-kB from its resting state to its active state (Ruberg, 1996). As an
activated molecule, it moves easily into the cell's nucleus and binds
to genes, allowing transcription of the target genes. This
"translocation" into the nucleus is a response to the oxidative
environment. Since the cell has already depleted its supply of
protective glutathione, the oxidative stresses catapult the NF-kB into
action (Fiers, 1995). While NF-kB targets genes involved in the immune
response, it also activates HIV. A piece of HIV called the Long
Terminal Repeat (see the HIV Replication Cycle section of TIP)--or
LTR--presents a target for the NF-kB to bind. Once bound, the LTR
begins the process of transcribing new virions.
Because dihydrolipoic acid is such an effective free radical
scavenger, it is postulated that dihydrolipoic acid makes up for the
lack of glutathione scavenging, thus preventing NF-kB activation (Han,
1995). NF-kB in the cytoplasm is a complex of proteins, including the
inhibitory protein IkB. When free radicals cause IkB to dissociate
from the parent complex, NF-kB transforms its shape and becomes able
to pass into the nucleus to activate its target genes (Passwater,
1995). Additionally, there is evidence that alpha-lipoic acid itself
interferes with NF-kB's binding sites to DNA. Therefore, even when
NF-kB becomes activated, the unreduced form of alpha-lipoic acid can
prevent DNA transcription. This is where the small size of
alpha-lipoic acid becomes crucially important; it can act within the
cellular nucleus as well as the cytoplasm in blocking NF-kB-activated
HIV replication (Passwater, 1995; Suzuki, 1992).
Historical/Traditional Use
Alpha-lipoic acid has been used for numerous physiological problems
since its properties were uncovered more fully in the 1960s. It is
used as a crisis intervention antidote for mushroom poisoning by
Amanita phalloides and A. virosa and has noted use for
polyneuropathies such as diabetic neuropathy (Piering, 1990; Becker,
1976). It has been used for patients with alcohol-related liver
disease and other liver disorders (Thompson, 1980) and has been used
by PWAs since 1991--first as a liver supportive and then as an
antioxidant (Hernandez, 1991).
Anecdotal/Informal Community Use
As noted above, alpha-lipoic acid was brought to the attention of the
HIV/AIDS community as an extremely effective liver supportive
medication to aid those with chronic and acute liver pathologies so
common among PWHIV. It is frequently used in conjunction with
silymarin 80% for liver inflammation. Some PWAs have also reported
that it has helped to control neuropathy.
More evidence of alpha-lipoic acid's effectiveness in normalizing the
excess quantity of free radicals in PWHIV was discovered between 1991
and 1995. Because of alpha-lipoic acid's low cost relative to its
powerful antiviral/antioxidant properties, it is becoming a
cornerstone in broad spectrum, non-toxic nutrient/ antioxidant
regimens, also valuable for detoxifying drug regimens. Along with NAC
it is also the only substance known to dramatically increase
glutathione levels in vivo--and not just in the laboratory. Its small
size allows it to penetrate cells, possibly making it the only
substance that has the direct potential to increase intracellular
glutathione levels.
Is It Toxic?
Toxicity studies have shown that alpha-lipoic acid is not known to be
toxic in therapeutic doses nor does it have any serious side effects.
It only becomes lethal (as any substance could) when it is highly
overloaded in mice (Baur, 1991; Fuke, 1972). In uncontrolled studies
of higher doses (600 mg/day and above), a few patients showed a slight
lowering of blood glucose levels and allergic skin reactions.
Controlled studies did not show any of these minor side effects.
Alpha-lipoic acid is not known to be cancer causing (mutagenic,
teratogenetic or carcinogenic) (Natureworks Educational Services,
1995).
What Are the Best Forms?
Alpha-lipoic acid is extremely stable and not highly reactive with
atmospheric oxygen. DAAIR sells the purest form available.
What Questions Remain?
If taken in combination with vitamins C and E, NAC and selenium, etc.,
will lipoic acid (a) reduce HIV load; (b) improve intracellular
glutathione levels; or (c) normalize levels of inflammatory cytokines
like TNF-alpha, IL-1 and IL-6? Will supplementation help to offset
liver damage induced by drugs used by PWHIV? Will supplementation help
to offset peripheral neuropathy? Will supplementation help to offset
development of kidney stones in those who use the protease inhibitor
indinavir (Crixivan) (Jayanthi, 1992)?
What Forms Does DAAIR Sell and Why?
DAAIR sells the highest grade alpha-lipoic acid available, which is
manufactured by ASTA Pharmaceuticals in Germany and put in tablet form
by Jarrow Formulas in 100mg/60 tablet bottles.
How Should I Take Alpha-Lipoic Acid?
Recommended dosage is 300 mg to a maximum of 600 mg per day with or
without meals. The 300 mg dose is good for those interested in its
broad-ranging antioxidant capabilities. The higher dose is used to
offset liver impairments. It had been previously thought that
alpha-lipoic acid should be taken with lipid-soluble thiamine
(tetrahydrofurfuryl thiamine, a form of vitamin B1) to aid in
absorption, but no confirmation of this has been noted in research
studies.
How Do I Find Out More? General Comments Section:
Given lipoic acid's value as an antioxidant, its ability to replenish
glutathione, and its liver protective functions, DAAIR feels that this
micronutrient should be a cornerstone of every PWHIV's protocol at any
stage of infection.
References:
Bast A, Haenen GRMM. Regulation of lipid peroxidation by glutathione
and lipoic acid: involvement of liver microsomal vitamin E reductase.
Antioxidants in therapy and preventative medicine. Emerit, J., et al.
eds; New York, Plenum Press, 1990.
Baur A, Harrer T, et al. Alpha-lipoic acid is an effective inhibitor
of human immunodeficiency virus (HIV-1) replication. Klinische
Wochenschrift. 69:722--724, 1991.
Becker CE, et al. Diagnosis and treatment of Amanita phalloides-type
mushroom poisoning: Use of thioctic acid. Western Journal of Medicine.
125:100--109, 1976.
Buhl R, et al. Systemic glutathione deficiency in symptom-free
HIV-seropositive people. Lancet, 1989;8675:1294-1298.
Busse E, et al. Influence of a[alpha]-lipoic acid on intracellular
glutathione in vitro and in vivo. Arzneimittelforschung.
1992;42(6):829--831.
Droge W, et al. Abnormal amino-acid concentrations in the blood of
patients with acquired immunodeficiency syndrome (AIDS) may contribute
to the immunological defect. Biol Chem Hoppe-Seyler, 1988;369:143-48.
Eck HP, et al. Low concentrations of acid-soluble thiol (cysteine) in
the blood plasma of HIV-1 infected patients. Biol Chem Hoppe-Seyler,
1989;370:101-108.
Fiers W. TNF: Intracellular mechanisms of action. HIV/Cytokines
(conference held in Reims, France, March 15-17, 1995) 1995;:abstract
E8.
Fuchs J, et al. Studies on lipoate effects of blood redox state in
human immunodeficiency virus infected patients. Arzneimittelforschung.
1993;43(12):1359--1362.
Fuke H, et al. Acute, subacute and chronic toxicities of thioctic acid
in rats. Folia Pharmacol. Japon. 1972;68:265--275.
Han D, Tritschler HJ, Packer L, a[alpha] Lipoic Acid Increases
Intracellular Glutathione in a Human T-lymphocyte Jurkat Cell Line.
Biochemical and Biophysical Research Communications.
1995;207(1):258--264.
Hernandez V, Thioctic Acid--A hepato-protective nutrient. Published by
ACT UP/NY, 3 pp., 1991.
Jayanthi S, Varalakshmi P. Tissue lipids in experimental calcium
oxalate lithiasis and the effect of DL alpha-lipoic acid. Biochem Int
1992;26(5):913-921.
Kagan VE, et al. Antioxidant action of thioctic acid and dihydrolipoic
acid. Free Radical Biol. Med. 1991;9: supplement 1:15.
Kagan VE, et al. Recycling of vitamin E in human low density
lipoproteins. Journal of Lipid Research. 1992;33:385--397.
Kis K, Meier T, Multhoff G, et al. Lipoate modulation of lymphocyte
cysteine uptake. Ox Stress and Redox Reg, May 21-24, 1996;:205.
Natureworks Educational Services: Alpha-lipoic Acid Fact Book. New
York: Abkit, Inc., 1995.
Passwater RA, Lipoic Acid Against AIDS: An interview with Dr. Lester
Packer. Whole Foods. December 1995:50--60.
Piering WF, and Bratanow N. Role of the clinical laboratory in guiding
treatment of Amanita virosa mushroom poisoning: report of two cases.
Clinical Chemistry. 1990;36(3):571--574.
Ruberg M. Parkinson's disease, apoptosis and oxidative stress. Ox
Stress and Redox Reg, May 21-24, 1996;:108.
Saliou C, Okamoto T, Traber MG, et al. Vitamin E and thiols exert
synergistic effects in the inhibition of TNF-alpha-induced HIV
replication in a human monocyte cell line. Ox Stress and Redox Reg,
May 21-24, 1996;:253.
Staal FJT, et al. Intracellular glutathione levels in T cell subsets
decrease in HIV-infected individuals. AIDS Res and Hum Retro,
1992;8(2):305-311.
Suzuki YJ, and Packer L. Inhibition of NF-kappa B DNA binding by
alpha-lipoic acid. Int Conf AIDS, 1994; 10(2) (abstract no. 401A).
Suzuki YJ, et al. Alpha-lipoic acid is a potent inhibitor of NF-kappa
D activation in human T cells. Biochem Biophys Res Commun.
1992;189(3):1709--1715.
Thompson AD, et al. Observations on hepato-protective drugs in
alcoholic liver disease. British Journal Of Alcohol. 1980;15:58--77.
Antiviral, Antioxidant for HIV and Liver Disease
(Special thanks to Mark Kuebel for his invaluable help in researching
and writing this Information Sheet)
What Is It?
Alpha-lipoic acid, also commonly called Thioctic acid, is fast
becoming recognized as another treatment for HIV disease which plays
several roles and addresses different problems. It is a small,
sulfur-containing molecule that easily passes into cells from the
bloodstream and is both water and fat soluble. Thioctic acid is
produced in extremely small quantities by cells, where it acts as a
coenzyme in production of energy molecules (known as ATP) from food. A
coenzyme is a substance that activates enzymes; the enzymes then help
to speed up reactions between other molecules. When supplemented,
thioctic acid is also a very powerful antioxidant outside of its
normal role in energy production.
The existence of alpha-lipoic acid was first suspected in
1937--researchers recognized that some as yet unidentified chemical
was involved in certain chemical reactions and was characterized in
1957. It is an integral coenzyme of mitochondrial production of ATP
from glucose, water and oxygen as part of the Kreb's (citric acid)
cycle. It naturally occurs tightly bound within mitochondria and is
not typically found in the cell fluid (cytoplasm) or other cellular
organelles (e.g., the nucleus). Supplementation increases its
availability for other cell parts, like inside the nucleus or in the
main part of the cytoplasm.
The alpha-lipoic acid molecule itself is a single-chain fatty acid
based on octanoic (or caprylic) acid--one of the constituents of
butter fat, for example, when the molecules are separated
(hydrolyzed). Lipoic acid is different from octanoic acid by virtue of
the sulfur atoms it has. It is the disulfide of two dihydrolipoate
molecules connected together at the sulfur bridge (like cystine is two
cysteines connected together). Because it is a small molecule, it
passes easily through biological membranes and is soluble in both
aqueous (water) and lipid (fat) environments. It gets into just about
all tissues, including the brain. This allows alpha-lipoic acid to
penetrate the nuclear envelope as well as the cytoplasm. Thus, it
operates within a cell's nucleus, in cytoplasm and can be found in
blood and in interstitial spaces (in the spaces within organs or
tissues) (Passwater, 1995).
Are There Deficiencies in HIV Infection?
Alpha-lipoic acid is not known to be deficient in HIV disease.
However, studies have yet to determine this. Naturally occurring
alpha-lipoic acid exists in energy-producing cell structures called
mitochondria, where it remains tightly bound. Mitochondria float
around in cells and change sugar into ATP, which is the most common
energy molecule of cells. Alpha-lipoic acid is used by enzymes in this
energy-production system in minute quantities, along with carnitine,
coenzyme Q10 and other players. The mechanism for alpha-lipoic acid
production in cells has yet to be fully explained, and all
alpha-lipoic acid produced for supplementation is made synthetically.
It should be noted that one type of damage done by AZT is to cellular
mitochondria.
Studies (Laboratory, Animal, Human)
Alpha-lipoic acid's primary feature--separating it from other
antioxidants--is its exceptional ability to act as a reducing agent.
This means it more readily donates electrons to molecules with a net
positive charge than many antioxidants and is easily recycled back to
its reduced state by intracellular glutathione reductase. The main
task of this enzyme is to transform oxidized glutathione (GSSG) back
to the active reduced form, GSH. This recycling mechanism is not
nearly as efficient in recycling alpha-lipoic acid, but it
significantly adds to the appeal of using it as a treatment for
oxidative stress (Passwater, 1995).
Through this antioxidant action, alpha-lipoic acid helps to keep
NF-kB, a cellular protein which activates HIV expression (see below).
Other features of alpha-lipoic acid important to PWAs are its ability
to aid in the recycling of vitamins C and E; its ability to replace
lost glutathione in intracellular free radical defense; and its
ability to reduce or eliminate plaque formation (clumping) of CD4
lymphocytes (syncytia), which is a suspected mechanism in the killing
of uninfected T cells (Passwater, 1995; Suzuki, 1994; Suzuki, 1992).
When alpha-lipoic acid (which is considered its oxidized state) enters
a typical cell, most of it is reduced to dihydrolipoic acid, which has
greater potential than alpha-lipoic acid to neutralize reactive oxygen
species. Dihydrolipoic acid has the same backbone structure as
alpha-lipoic acid, except its disulfide connection is broken (Bast,
1990). Another metabolic product that comes from alpha-lipoic acid is
tetranorlipoic acid, which has been shown to be very potent for
inhibition of NF-kB (Suzuki, 1994). Through Suzuki and Packer's work,
it is evident that two portions of this molecule are active in
inhibiting NF-kB, including the hydrocarbon backbone and the cyclic
disulfide side chain. The cyclic disulfide/dual SH- moieties (parts)
are much more potent than the hydrocarbon chain. (The sulfhydryl group
[SH] donates two hydrogen ions [protons denoted H-] to reduce oxidant
molecules. Again, because repetition is good for the soul, the
dihydrolipoate is oxidized, and a disulfide bridge forms between the
two sulfur atoms to form the cyclic compound alpha-lipoic acid.)
Alpha-lipoic acid has also been shown to aid in the recycling of
reduced vitamin C and, thereby, vitamin E. Alpha-lipoic acid reduces
dehydroascorbate (oxidized ascorbate) back to vitamin C, which in turn
reduces vitamin E. This maintains a steady state of both vitamins C
and E (Kagan, 1992; Passwater, 1995). When Kagan's group added
dihydrolipoate acid to a mixture of plasma lipoproteins (a fat-protein
mixture that mimics a cell's membrane) undergoing peroxidation
(oxidative stress), the ability of ascorbate to recycle vitamin E
increased greatly. Thus there was more vitamin E available in a form
that was effective in limiting the damage to cellular membranes
induced by the oxidative stress. This effect was shown in other test
situations with liposomes (balls of fat), microsomes (balls composed
of a cellular organ, the endoplasmic reticulum), membranes and tissue
homogenates (blended tissues) (Kagan, 1991).
The role of glutathione as the primary cellular antioxidant, and its
often extreme deficiency in people with HIV, cannot be overemphasized
when discussing the use of antioxidant therapy for HIV/AIDS. (Please
see the Glutathione Information Sheet). Alpha-lipoic acid has the
ability to recycle oxidized glutathione (GSSG) back to reduced
glutathione (GSH), possibly by simply donating electrons to GSSG
(although the mechanism is not clear). Alpha-lipoic acid in turn, is
then reduced by glutathione reductase and other enzymes. Because
intracellular alpha-lipoic acid concentrations are in the range of
nanomoles (nM, extremely low concentration) and glutathione is in the
range of millimoles (mM, which is relatively high), the recycling of
alpha-lipoic acid takes place without interfering with the recycling
of GSSG to GSH (Kis, 1996).
In fact, the concentration of glutathione in the cytoplasm is among
the highest of any substance in healthy tissues and alpha lipoic acid
can improve this level. A pilot study in people with AIDS (CDC stage
IV) has confirmed the in vitro studies of alpha-lipoic acid's
abilities to recycle cellular antioxidants and vitamins with 100%
response rate for increased total glutathione (7 of 7 patients).
Increases in vitamin C were also noted in 9 of 10, while a decrease in
markers of lipid peroxidation was shown in most patients (7 of 9 for
the marker, 4-hydroxynonenal and in 8 of 9 for malondialdehyde). CD4
counts and CD4/CD8 ratios were improved in 6 of 10 (Fuchs, 1993).
The increase of cellular GSH in T-lymphocyte Jurkat cells is induced
by an increase in lipoate concentration and is not dependent on the
synthesis of enzymes that may synthesize glutathione. It appears to be
a direct effect of lipoic acid (as dihydrolipoic acid) on GSSG (Han,
1995; Passwater, 1995). Because GSH protects against lipid
peroxidation and plays a "pivotal role" in maintaining membrane
integrity both inside cells and the plasma membrane itself (Bast,
1990), any drop in GSH levels may effect physiological exchanges that
take place across lipid membranes, like the absorption of nutrients
from blood, oxygenation of cytoplasm, and a myriad of other processes.
(Please review the Information Sheet on Glutathione.)
A test tube study compared the effects of fat-soluble antioxidants
(e.g., vitamin E) to water-soluble antioxidants (like alpha-lipoic
acid) to determine their effect on the amount of HIV produced by
monocytes. Such studies traditionally have used concentrations that
are beyond what can be obtained physiologically--that is, you'd have
to wolf down huge quantities to have any effect. When they used a more
reasonable concentration, they found a small inhibition--a 30%
reduction in expression. However, when they mixed the water-soluble
and fat-soluble vitamins together, they saw a much more substantial
inhibition of 50 to 80% (Saliou, 1996). Another study is being
conducted in the United States to determine if there is efficacy in
treating HIV-related dementia (protocol number FDA 250A) and plans are
being discussed at AmFAR for a (more sensible?) approach of using a
combination to improve liver function.
How Does It Work and How Does It Work in HIV Infection?
Because it can pass into cells easily, alpha-lipoic acid acts as an
antioxidant in all parts of cells and tissues, thereby slowing the
damaging effects of HIV and other oxidant-generating toxins, viruses
and bacteria. But most importantly, it can slow the multiplication of
HIV. Many antioxidants do their primary work in the bloodstream, but
alpha-lipoic acid has the ability to penetrate all areas of cells,
meaning it can work in the cell's nucleus where HIV resides and
multiplies (Passwater, 1995). Thus, it gets into tissues that some
drugs do not reach.
Human cells do not use alpha-lipoic acid as a broad-spectrum
antioxidant; instead, they use the less powerful molecule glutathione.
Glutathione is a cell's most important naturally-occurring antioxidant
defense and is also chronically deficient in people with HIV. The
antioxidant properties of alpha-lipoic acid can be broadened to the
entire body when taken as a supplement, helping to make up for
HIV-caused deficiency of glutathione (Busse, 1992; Han, 1995).
Alpha-lipoic acid is an agent that reduces the oxidizing strength of
molecules. Therefore, it is able to "soothe" oxidant molecules that
cause inflammation and cell membrane damage throughout the body. This
effect neutralizes the oxidant molecules, keeping them from causing
their usual damage. Normally, this is done by glutathione, but
glutathione is deficient in PWHIV (Buhl, 1989; Droge, 1988; Eck, 1989;
Staal, 1992). Because much inflammation associated with HIV is caused
by oxidative stress, use of antioxidant supplements like vitamin C,
bioflavonoids, NAC, vitamin E, beta carotene, amino acids,
glycyrrhizin and others are an important strategy in reducing
degrading effects of HIV infection. Alpha-lipoic acid has now been
added to this list of antioxidants. Not only does it recycle the
important antioxidants glutathione, vitamin C and vitamin E, but it
also helps to turn off the pathway in HIV-infected cells that turns on
HIV multiplication (Passwater, 1995).
Because of its strong reducing properties, alpha-lipoic acid also
helps prevent the activation of HIV multiplication in HIV-infected
cells (Baur, 1991). The second function of alpha-lipoic acid in
stopping viral replication is a complicated process. In simple terms,
alpha-lipoic acid prevents an infected cell from turning on the genes
of HIV in the cell nucleus. The insidious nature of HIV is such that
it incorporates itself into the genes of HIV-infected cells, actually
becoming part of a human gene. Genes need triggers from the cell to
turn on the production of new proteins from the genetic code. A
special molecular complex called nuclear factor kappa B (NF-kB) is the
complex that turns on HIV genes (and other genes) in an infected
cell's nucleus. Oxidants in the cell not scavenged by glutathione
activate the NF-kB to turn on HIV multiplication. Alpha-lipoic acid
prevents this by keeping oxidants cleaned up inside the cell, thereby
keeping NF-kB from being stimulated (Suzuki, 1992). Thus, HIV remains
dormant in the genes, oxidants are neutralized, and the cell remains
alive and healthy. (See the Immunology Primer and the first sections
of the DAAIR TIP.)
NF-kB is a gene activator protein that resides in a cell's cytoplasm.
Free radical damage in a cell will often trigger the transformation of
NF-kB from its resting state to its active state (Ruberg, 1996). As an
activated molecule, it moves easily into the cell's nucleus and binds
to genes, allowing transcription of the target genes. This
"translocation" into the nucleus is a response to the oxidative
environment. Since the cell has already depleted its supply of
protective glutathione, the oxidative stresses catapult the NF-kB into
action (Fiers, 1995). While NF-kB targets genes involved in the immune
response, it also activates HIV. A piece of HIV called the Long
Terminal Repeat (see the HIV Replication Cycle section of TIP)--or
LTR--presents a target for the NF-kB to bind. Once bound, the LTR
begins the process of transcribing new virions.
Because dihydrolipoic acid is such an effective free radical
scavenger, it is postulated that dihydrolipoic acid makes up for the
lack of glutathione scavenging, thus preventing NF-kB activation (Han,
1995). NF-kB in the cytoplasm is a complex of proteins, including the
inhibitory protein IkB. When free radicals cause IkB to dissociate
from the parent complex, NF-kB transforms its shape and becomes able
to pass into the nucleus to activate its target genes (Passwater,
1995). Additionally, there is evidence that alpha-lipoic acid itself
interferes with NF-kB's binding sites to DNA. Therefore, even when
NF-kB becomes activated, the unreduced form of alpha-lipoic acid can
prevent DNA transcription. This is where the small size of
alpha-lipoic acid becomes crucially important; it can act within the
cellular nucleus as well as the cytoplasm in blocking NF-kB-activated
HIV replication (Passwater, 1995; Suzuki, 1992).
Historical/Traditional Use
Alpha-lipoic acid has been used for numerous physiological problems
since its properties were uncovered more fully in the 1960s. It is
used as a crisis intervention antidote for mushroom poisoning by
Amanita phalloides and A. virosa and has noted use for
polyneuropathies such as diabetic neuropathy (Piering, 1990; Becker,
1976). It has been used for patients with alcohol-related liver
disease and other liver disorders (Thompson, 1980) and has been used
by PWAs since 1991--first as a liver supportive and then as an
antioxidant (Hernandez, 1991).
Anecdotal/Informal Community Use
As noted above, alpha-lipoic acid was brought to the attention of the
HIV/AIDS community as an extremely effective liver supportive
medication to aid those with chronic and acute liver pathologies so
common among PWHIV. It is frequently used in conjunction with
silymarin 80% for liver inflammation. Some PWAs have also reported
that it has helped to control neuropathy.
More evidence of alpha-lipoic acid's effectiveness in normalizing the
excess quantity of free radicals in PWHIV was discovered between 1991
and 1995. Because of alpha-lipoic acid's low cost relative to its
powerful antiviral/antioxidant properties, it is becoming a
cornerstone in broad spectrum, non-toxic nutrient/ antioxidant
regimens, also valuable for detoxifying drug regimens. Along with NAC
it is also the only substance known to dramatically increase
glutathione levels in vivo--and not just in the laboratory. Its small
size allows it to penetrate cells, possibly making it the only
substance that has the direct potential to increase intracellular
glutathione levels.
Is It Toxic?
Toxicity studies have shown that alpha-lipoic acid is not known to be
toxic in therapeutic doses nor does it have any serious side effects.
It only becomes lethal (as any substance could) when it is highly
overloaded in mice (Baur, 1991; Fuke, 1972). In uncontrolled studies
of higher doses (600 mg/day and above), a few patients showed a slight
lowering of blood glucose levels and allergic skin reactions.
Controlled studies did not show any of these minor side effects.
Alpha-lipoic acid is not known to be cancer causing (mutagenic,
teratogenetic or carcinogenic) (Natureworks Educational Services,
1995).
What Are the Best Forms?
Alpha-lipoic acid is extremely stable and not highly reactive with
atmospheric oxygen. DAAIR sells the purest form available.
What Questions Remain?
If taken in combination with vitamins C and E, NAC and selenium, etc.,
will lipoic acid (a) reduce HIV load; (b) improve intracellular
glutathione levels; or (c) normalize levels of inflammatory cytokines
like TNF-alpha, IL-1 and IL-6? Will supplementation help to offset
liver damage induced by drugs used by PWHIV? Will supplementation help
to offset peripheral neuropathy? Will supplementation help to offset
development of kidney stones in those who use the protease inhibitor
indinavir (Crixivan) (Jayanthi, 1992)?
What Forms Does DAAIR Sell and Why?
DAAIR sells the highest grade alpha-lipoic acid available, which is
manufactured by ASTA Pharmaceuticals in Germany and put in tablet form
by Jarrow Formulas in 100mg/60 tablet bottles.
How Should I Take Alpha-Lipoic Acid?
Recommended dosage is 300 mg to a maximum of 600 mg per day with or
without meals. The 300 mg dose is good for those interested in its
broad-ranging antioxidant capabilities. The higher dose is used to
offset liver impairments. It had been previously thought that
alpha-lipoic acid should be taken with lipid-soluble thiamine
(tetrahydrofurfuryl thiamine, a form of vitamin B1) to aid in
absorption, but no confirmation of this has been noted in research
studies.
How Do I Find Out More? General Comments Section:
Given lipoic acid's value as an antioxidant, its ability to replenish
glutathione, and its liver protective functions, DAAIR feels that this
micronutrient should be a cornerstone of every PWHIV's protocol at any
stage of infection.
References:
Bast A, Haenen GRMM. Regulation of lipid peroxidation by glutathione
and lipoic acid: involvement of liver microsomal vitamin E reductase.
Antioxidants in therapy and preventative medicine. Emerit, J., et al.
eds; New York, Plenum Press, 1990.
Baur A, Harrer T, et al. Alpha-lipoic acid is an effective inhibitor
of human immunodeficiency virus (HIV-1) replication. Klinische
Wochenschrift. 69:722--724, 1991.
Becker CE, et al. Diagnosis and treatment of Amanita phalloides-type
mushroom poisoning: Use of thioctic acid. Western Journal of Medicine.
125:100--109, 1976.
Buhl R, et al. Systemic glutathione deficiency in symptom-free
HIV-seropositive people. Lancet, 1989;8675:1294-1298.
Busse E, et al. Influence of a[alpha]-lipoic acid on intracellular
glutathione in vitro and in vivo. Arzneimittelforschung.
1992;42(6):829--831.
Droge W, et al. Abnormal amino-acid concentrations in the blood of
patients with acquired immunodeficiency syndrome (AIDS) may contribute
to the immunological defect. Biol Chem Hoppe-Seyler, 1988;369:143-48.
Eck HP, et al. Low concentrations of acid-soluble thiol (cysteine) in
the blood plasma of HIV-1 infected patients. Biol Chem Hoppe-Seyler,
1989;370:101-108.
Fiers W. TNF: Intracellular mechanisms of action. HIV/Cytokines
(conference held in Reims, France, March 15-17, 1995) 1995;:abstract
E8.
Fuchs J, et al. Studies on lipoate effects of blood redox state in
human immunodeficiency virus infected patients. Arzneimittelforschung.
1993;43(12):1359--1362.
Fuke H, et al. Acute, subacute and chronic toxicities of thioctic acid
in rats. Folia Pharmacol. Japon. 1972;68:265--275.
Han D, Tritschler HJ, Packer L, a[alpha] Lipoic Acid Increases
Intracellular Glutathione in a Human T-lymphocyte Jurkat Cell Line.
Biochemical and Biophysical Research Communications.
1995;207(1):258--264.
Hernandez V, Thioctic Acid--A hepato-protective nutrient. Published by
ACT UP/NY, 3 pp., 1991.
Jayanthi S, Varalakshmi P. Tissue lipids in experimental calcium
oxalate lithiasis and the effect of DL alpha-lipoic acid. Biochem Int
1992;26(5):913-921.
Kagan VE, et al. Antioxidant action of thioctic acid and dihydrolipoic
acid. Free Radical Biol. Med. 1991;9: supplement 1:15.
Kagan VE, et al. Recycling of vitamin E in human low density
lipoproteins. Journal of Lipid Research. 1992;33:385--397.
Kis K, Meier T, Multhoff G, et al. Lipoate modulation of lymphocyte
cysteine uptake. Ox Stress and Redox Reg, May 21-24, 1996;:205.
Natureworks Educational Services: Alpha-lipoic Acid Fact Book. New
York: Abkit, Inc., 1995.
Passwater RA, Lipoic Acid Against AIDS: An interview with Dr. Lester
Packer. Whole Foods. December 1995:50--60.
Piering WF, and Bratanow N. Role of the clinical laboratory in guiding
treatment of Amanita virosa mushroom poisoning: report of two cases.
Clinical Chemistry. 1990;36(3):571--574.
Ruberg M. Parkinson's disease, apoptosis and oxidative stress. Ox
Stress and Redox Reg, May 21-24, 1996;:108.
Saliou C, Okamoto T, Traber MG, et al. Vitamin E and thiols exert
synergistic effects in the inhibition of TNF-alpha-induced HIV
replication in a human monocyte cell line. Ox Stress and Redox Reg,
May 21-24, 1996;:253.
Staal FJT, et al. Intracellular glutathione levels in T cell subsets
decrease in HIV-infected individuals. AIDS Res and Hum Retro,
1992;8(2):305-311.
Suzuki YJ, and Packer L. Inhibition of NF-kappa B DNA binding by
alpha-lipoic acid. Int Conf AIDS, 1994; 10(2) (abstract no. 401A).
Suzuki YJ, et al. Alpha-lipoic acid is a potent inhibitor of NF-kappa
D activation in human T cells. Biochem Biophys Res Commun.
1992;189(3):1709--1715.
Thompson AD, et al. Observations on hepato-protective drugs in
alcoholic liver disease. British Journal Of Alcohol. 1980;15:58--77.
