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"Iron-binding alpha-lipoic acid"

The Journal of Alternative and Complementary Medicine
Restoration of Blood Total Glutathione Status and Lymphocyte Function
Following α-Lipoic Acid Supplementation in Patients with HIV Infection

Raxit J. Jariwalla, Ph.D.
California Institute for Medical Research, San Jose, CA
Currently at Dr. Rath Research Institute, Santa Clara, CA.
Jacob Lalezari, M.D.
Quest Clinical Research, San Francisco, CA.
Diane Cenko, M.A.
Quest Clinical Research, San Francisco, CA.
Saint Francis Memorial Hospital, San Francisco, CA.
Sam E. Mansour, M.D.
Eye Clinic, Santa Clara Valley Medical Center, San Jose, CA.
Currently at the Virginia Retina Center, Leesburg, VA.
Abha Kumar, M.D.
Eye Clinic, Santa Clara Valley Medical Center, San Jose, CA.
Bhakti Gangapurkar, B.A.
California Institute for Medical Research, San Jose, CA
Currently at Dr. Rath Research Institute, Santa Clara, CA.
Daniel Nakamura, M.S.E.E.
California Institute for Medical Research, San Jose, CA
Currently in San Bruno, CA.
ABSTRACT

Objectives: To determine whether supplementation with α-lipoic acid
(ALA), a glutathione-replenishing disulfide, modulates whole blood
total glutathione (GSH + GSSG) levels and improves lymphocyte function
in human immunodeficiency virus (HIV)-infected subjects with history
of unresponsiveness to highly active antiretroviral treatment (HAART).

Design and setting: Randomized, double-blinded, placebo-controlled
trial conducted at two study sites: an eye clinic at a county hospital
in San Jose and a research clinic in San Francisco, California.

Subjects: A total of 33 HIV-infected men and women with viral load >
10,000 copies/cm3, despite HAART, aged 44–47 years, approximately 36%
nonwhite, were enrolled.

Intervention: Patients were randomly assigned to receive either ALA
(300 mg three times a day) or matching placebo for 6 months.

Main outcome measures: The change over 6 months in blood total
glutathione status, lymphocyte proliferation response to T-cell
mitogens, CD4 cell count, and viral load in patients receiving ALA
compared to placebo.

Results: The mean blood total glutathione level in ALA-supplemented
subjects was significantly elevated after 6 months (1.34 ± 0.79 vs.
0.81 ± 0.18 mmol/L) compared to insignificant change (0.76 ± 0.34 vs.
0.76 ± 0.22 mmol/L) in the placebo group (ALA vs. placebo: p = 0.04).
The lymphocyte proliferation response was significantly enhanced or
stabilized after 6 months of ALA supplementation compared to
progressive decline in the placebo group (ALA vs. placebo: p < 0.001
with phytohemagglutinin; p = 0.02 with anti-CD3 monoclonal antibody).
A positive correlation was seen between blood total glutathione level
and lymphocyte response to anti-CD3 stimulation (R2 = 0.889). There
was no significant change in either HIV RNA level or CD4 count over 6
months in the ALA-supplemented compared to the control group.

Conclusion: Supplementation with α-lipoic acid may positively impact
patients with HIV and acquired immune deficiency syndrome by restoring
blood total glutathione level and improving functional reactivity of
lymphocytes to T-cell mitogens.

To cite this paper:
Raxit J. Jariwalla, Jacob Lalezari, Diane Cenko, Sam E. Mansour, Abha
Kumar, Bhakti Gangapurkar, Daniel Nakamura. The Journal of Alternative
and Complementary Medicine. March 1, 2008, 14(2): 139-146. doi:10.1089/
acm.2006.6397.

-------------------
Iron-binding drugs targeted to lysosomes: a potential strategy to
treat inflammatory lung disorders.
Expert Opin Investig Drugs. 2005 Aug;14(8):997-1008.
Persson HL, Richardson DR.
Division of Pulmonary Medicine, Faculty of Health Sciences, University
of Linköping, SE-581 85 Linköping, Sweden. Lenpe@inr.liu.se

In many inflammatory lung disorders, an abnormal assimilation of redox-
active iron will exacerbate oxidative tissue damage.
It may be that the most important cellular pool of redox-active iron
exists within lysosomes, making these organelles vulnerable to
oxidative stress.
In experiments employing respiratory epithelial cells and macrophages,
the chelation of intra-lysosomal iron efficiently prevented lysosomal
rupture and the ensuing cell death induced by hydrogen peroxide,
ionising radiation or silica particles. Furthermore, cell-permeable
iron-binding agents (weak bases) that accumulate within lysosomes due
to proton trapping were much more efficient for cytoprotection than
the chelator, desferrioxamine. On a molar basis, the weak base alpha-
lipoic acid plus was 5000 times more effective than desferrioxamine at
preventing lysosomal rupture and apoptotic cell death in cell cultures
exposed to hydrogen peroxide.
Thus, iron-chelating therapy that targets the lysosome might be a
future treatment strategy for inflammatory pulmonary diseases.

PMID: 16050792

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http://www.imminst.org/forum/index.php?act=ST&f=6&t=11594&hl=12726917&s=

Prevention of oxidant-induced cell death by lysosomotropic iron
chelators.

* Persson HL,
* Yu Z,
* Tirosh O,
* Eaton JW,
* Brunk UT.

Division of Pathology II, Faculty of Health Sciences, University
of Linkoping, Linkoping, Sweden. Lennart.Persson@lio.se

Intralysosomal iron powerfully synergizes oxidant-induced cellular
damage. The iron chelator, desferrioxamine (DFO), protects cultured
cells against oxidant challenge but pharmacologically effective
concentrations of this drug cannot readily be achieved in vivo. DFO
localizes almost exclusively within the lysosomes following endocytic
uptake, suggesting that truly lysosomotropic chelators might be even
more effective. We hypothesized that an amine derivative of alpha-
lipoamide (LM), 5-[1,2] dithiolan-3-yl-pentanoic acid (2-dimethylamino-
ethyl)-amide (alpha-lipoic acid-plus [LAP]; pKa = 8.0), would
concentrate via proton trapping within lysosomes, and that the vicinal
thiols of the reduced form of this agent would interact with
intralysosomal iron, preventing oxidant-mediated cell damage. Using a
thiol-reactive fluorochrome, we find that reduced LAP does accumulate
within the lysosomes of cultured J774 cells. Furthermore, LAP is
approximately 1000 and 5000 times more effective than LM and DFO,
respectively, in protecting lysosomes against oxidant-induced rupture
and in preventing ensuing apoptotic cell death. Suppression of
lysosomal accumulation of LAP (by ammonium-mediated lysosomal
alkalinization) blocks these protective effects. Electron paramagnetic
resonance reveals that the intracellular generation of hydroxyl
radical following addition of hydrogen peroxide to J774 cells is
totally eliminated by pretreatment with either DFO (1 mM) or LAP (0.2
microM) whereas LM (200 microM) is much less effective.

PMID: 12726917

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