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Alpha-Lipoic
acid: a metabolic antioxidant which regulates NF-kappa B signal
transduction and protects against oxidative injury.
Packer L.
Department of Molecular and Cell Biology, University of California,
Berkeley 94720-3200, USA.
Drug Metab Rev. 1998 May;30(2):245-75.
Although the metabolic role of alpha-lipoic acid
has been known for over 40 years, it is only recently that its
effects when supplied exogenously have become known. Exogenous
alpha-lipoic acid is reduced intracellularly by at least two and
possibly three enzymes, and through the actions of its reduced
form, it influences a number of cell process. These include direct
radical scavenging, recycling of other antioxidants, accelerating
GSH synthesis, and modulating transcription factor activity, especially
that of NF-kappa B (Fig. 12). These mechanisms may account for
the sometimes dramatic effects of alpha-lipoic acid in oxidative
stress conditions (e.g., brain ischemia-reperfusion), and point
the way toward its therapeutic use.
Neuroprotective effects of alpha-lipoic acid
and its positively charged amide analogue.
Tirosh O, Sen CK, Roy S, Kobayashi MS, Packer L.
Department of Molecular and Cell Biology, University of California,
Berkeley 94720-3200, USA.
Free Radic Biol Med. 1999 Jun;26(11-12):1418-26.
Elevated levels of extracellular glutamate have
been linked to reactive oxygen species mediated neuronal damage
and brain disorders. Lipoic acid is a potent antioxidant that
has previously been shown to exhibit neuroprotection in clinical
studies. A new positively charged water soluble lipoic acid amide
analog, 2-(N,N-dimethylamine) ethylamido lipoate HCl (LA-plus),
with a better cellular reduction and retention of the reduced
form was developed. This novel antioxidant was tested for protection
against glutamate induced cytotoxicity in a HT4 neuronal cell
line. Glutamate treatment for 12 h resulted in significant release
of LDH from cells to the medium suggesting cytotoxicity. Measurement
of intracellular peroxides showed marked (up to 200%) increase
after 6 h of glutamate treatment. Compared to lipoic acid, LA-plus
was more effective in (1) protecting cells against glutamate induced
cytotoxicity, (2) preventing glutamate induced loss of intracellular
GSH, and (3) disallowing increase of intracellular peroxide level
following the glutamate challenge. The protective effect of LA-plus
was found to be independent of its stereochemistry. The protective
function of this antioxidant was synergistically enhanced by selenium.
These results demonstrate that LA-plus is a potent protector of
neuronal cells against glutamate-induced cytotoxicity and associated
oxidative stress.
Lipoic acid confers protection against oxidative
injury in non-neuronal and neuronal tissue.
Lynch MA.
Department of Physiology, Trinity College Institute for Neuroscience,
Trinity College, Dublin, Ireland.
Nutr Neurosci. 2001;4(6):419-38.
In the past decade or so, a convincing link between
oxidative stress and degenerative conditions has been made and
with the knowledge that oxidatiye changes may actually trigger
deterioration in cell function, a great deal of energy has focussed
on identifying agents which may have possible therapeutic value
in combating oxidative changes. One agent which has received attention,
because of its powerful antioxidative effects, particularly in
neuronal tissue, is lipoic acid.
Lipoic (thioctic) acid increases brain energy
availability and skeletal muscle performance as shown by in vivo
31P-MRS in a patient with mitochondrial cytopathy.
Barbiroli B, Medori R, Tritschler HJ, Klopstock
T, Seibel P, Reichmann H, Iotti S, Lodi R, Zaniol P.
Cattedra di Biochimica Clinica, Istituto di Patologia Speciale
Medica D. Campanacci, Universita' di Bologna, Italy.
A woman affected by chronic progressive external ophthalmoplegia
and muscle mitochondrial DNA deletion was studied by phosphorus
magnetic resonance spectroscopy (31P-MRS) prior to and after 1
and 7 months of treatment with oral lipoic acid. Before treatment
a decreased phosphocreatine (PCr) content was found in the occipital
lobes, accompanied by normal inorganic phosphate (Pi) level and
cytosolic pH. Based on these findings, we found a high cytosolic
adenosine diphosphate concentration [ADP] and high relative rate
of energy metabolism together with a low phosphorylation potential.
Muscle MRS showed an abnormal work-energy cost transfer function
and a low rate of PCr recovery during the post-exercise period.
All of these findings indicated a deficit of mitochondrial function
in both brain and muscle. Treatment with 600 mg lipoic acid daily
for 1 month resulted in a 55% increase of brain [PCr], 72% increase
of phosphorylation potential, and a decrease of calculated [ADP]
and rate of energy metabolism. After 7 months of treatment MRS
data and mitochondrial function had improved further. Treatment
with lipoate also led to a 64% increase in the initial slope of
the work-energy cost transfer function in the working calf muscle
and worsened the rate of PCr resynthesis during recovery. The
patient reported subjective improvement of general conditions
and muscle performance after therapy. Our results indicate that
treatment with lipoate caused a relevant increase in levels of
energy available in brain and skeletal muscle during exercise.
Neuroprotection by the metabolic antioxidant
alpha-lipoic acid.
Packer L, Tritschler HJ, Wessel K.
Department of Molecular and Cell Biology, University of California,
Berkeley 94720-3200, USA.
Free Radic Biol Med. 1997;22(1-2):359-78.
Reactive oxygen species are thought to be involved
in a number of types of acute and chronic pathologic conditions
in the brain and neural tissue. The metabolic antioxidant alpha-lipoate
(thioctic acid, 1, 2-dithiolane-3-pentanoic acid; 1, 2-dithiolane-3
valeric acid; and 6, 8-dithiooctanoic acid) is a low molecular
weight substance that is absorbed from the diet and crosses the
blood-brain barrier. alpha-Lipoate is taken up and reduced in
cells and tissues to dihydrolipoate, which is also exported to
the extracellular medium; hence, protection is afforded to both
intracellular and extracellular environments. Both alpha-lipoate
and especially dihydrolipoate have been shown to be potent antioxidants,
to regenerate through redox cycling other antioxidants like vitamin
C and vitamin E, and to raise intracellular glutathione levels.
Thus, it would seem an ideal substance in the treatment of oxidative
brain and neural disorders involving free radical processes. Examination
of current research reveals protective effects of these compounds
in cerebral ischemia-reperfusion, excitotoxic amino acid brain
injury, mitochondrial dysfunction, diabetes and diabetic neuropathy,
inborn errors of metabolism, and other causes of acute or chronic
damage to brain or neural tissue. Very few neuropharmacological
intervention strategies are currently available for the treatment
of stroke and numerous other brain disorders involving free radical
injury. We propose that the various metabolic antioxidant properties
of alpha-lipoate relate to its possible therapeutic roles in a
variety of brain and neuronal tissue pathologies: thiols are central
to antioxidant defense in brain and other tissues. The most important
thiol antioxidant, glutathione, cannot be directly administered,
whereas alpha-lipoic acid can. In vitro, animal, and preliminary
human studies indicate that alpha-lipoate may be effective in
numerous neurodegenerative disorders. Scientific
abstracts
from Pubmed
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