Alpha-Lipoic Acid and Alcohol
||Differential effects of lipoic acid stereoisomers
on glucose metabolism in insulin-resistant skeletal muscle.
Streeper RS, Henriksen EJ, Jacob S, Hokama JY, Fogt DL, Tritschler
Department of Physiology, University of Arizona,
Tucson 85721-0093, USA.
The racemic mixture of the antioxidant alpha-lipoic acid (ALA)
enhances insulin-stimulated glucose metabolism in insulin-resistant
humans and animals. We determined the individual effects of the
pure R-(+) and S-(-) enantiomers of ALA on glucose metabolism in
skeletal muscle of an animal model of insulin resistance, hyperinsulinemia,
and dyslipidemia: the obese Zucker (fa/fa) rat. Obese rats were
treated intraperitoneally acutely (100 mg/kg body wt for 1 h) or
chronically [10 days with 30 mg/kg of R-(+)-ALA or 50 mg/kg of S-(-)-ALA].
Glucose transport [2-deoxyglucose (2-DG) uptake], glycogen synthesis,
and glucose oxidation were determined in the epitrochlearis muscles
in the absence or presence of insulin (13.3 nM). Acutely, R-(+)-ALA
increased insulin-mediated 2-DG-uptake by 64% (P < 0.05), whereas
S-(-)-ALA had no significant effect. Although chronic R-(+)-ALA
treatment significantly reduced plasma insulin (17%) and free fatty
acids (FFA; 35%) relative to vehicle-treated obese animals, S-(-)-ALA
treatment further increased insulin (15%) and had no effect on FFA.
Insulin-stimulated 2-DG uptake was increased by 65% by chronic R-(+)-ALA
treatment, whereas S-(-)-ALA administration resulted in only a 29%
improvement. Chronic R-(+)-ALA treatment elicited a 26% increase
in insulin-stimulated glycogen synthesis and a 33% enhancement of
insulin-stimulated glucose oxidation. No significant increase in
these parameters was observed after S-(-)-ALA treatment. Glucose
transporter (GLUT-4) protein was unchanged after chronic R-(+)-ALA
treatment but was reduced to 81 +/- 6% of obese control with S-(-)-ALA
treatment. Therefore, chronic parenteral treatment with the antioxidant
ALA enhances insulin-stimulated glucose transport and non-oxidative
and oxidative glucose metabolism in insulin-resistant rat skeletal
muscle, with the R-(+) enantiomer being much more effective than
the S-(-) enantiomer.
Alpha-Lipoic Acid and diabetes Scientific
|| Treatment of diabetic polyneuropathy with
the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter
randomized double-blind placebo-controlled trial (ALADIN II). Alpha
Lipoic Acid in Diabetic Neuropathy.
Reljanovic M, Reichel G, Rett K, Lobisch M, Schuette K, Moller W,
Tritschler HJ, Mehnert H.
University of Clinic for Diabetes, Endocrinology and Metabolic
Diseases Vuk Vrhovac, Medical faculty, University of Zagreb, Coratia.
Free Radic Res. 1999 Sep;31(3):171-9.
Short-term trials with the antioxidant thioctic acid (TA) appear
to improve neuropathic symptoms in diabetic patients, but the long-term
response remains to be established. Therefore, Type 1 and Type 2
diabetic patients with symptomatic polyneuropathy were randomly
assigned to three treatment regimens: (1) 2 x 600(mg of TA (TA 1200),
(2) 600)mg of TA plus placebo (PLA) (TA 600) or (3) placebo and
placebo (PLA). A trometamol salt solution of TA of 1200 or 600 mg
or PLA was intravenously administered once daily for five consecutive
days before enrolling the patients in the oral treatment phase.
The study was prospective, PLA-controlled, randomized, double-blind
and conducted for two years. Severity of diabetic neuropathy was
assessed by the Neuropathy Disability Score (NDS) and electrophysiological
attributes of the sural (sensory nerve conduction velocity (SNCV),
sensory nerve action potential (SNAP)) and the tibial (motor nerve
conduction velocity (MNCV), motor nerve distal latency (MNDL)) nerve.
Statistical analysis was performed after independent reviewers excluded
all patients with highly variable data allowing a final analysis
of 65 patients (TA 1200: n = 18, TA 600: n = 27; PLA: n = 20). At
baseline no significant differences were noted between the groups
regarding the demographic variables and peripheral nerve function
parameters for these 65 patients. Statistically significant changes
after 24 months between TA and PLA were observed (mean +/- SD) for
sural SNCV: +3.8 +/- 4.2 m/s in TA 1200, +3.0+/-3.0m/s in TA 600,
-0.1+/-4.8m/s in PLA (p < 0.05 for TA 1200 and TA 600 vs. PLA);
sural SNAP: +0.6+/-2.5 microV in TA 1200, +0.3+/-1.4 microV in TA
600, -0.7 +/- 1.5 microV in PLA (p = 0.076 for TA 1200 vs. PLA and
p < 0.05 for TA 600 vs. PLA), and in tibial MNCV: +/- 1.2 +/- 3.8
m/s in TA 1200, -0.3 +/- 5.2 m/s in TA 600, 1.5 +/- 2.9 m/s in PLA
(p < 0.05 for TA 1200 vs. PLA). No significant differences between
the groups after 24 months were noted regarding the tibial MNDL
and the NDS. We conclude that in a subgroup of patients after exclusion
of patients with excessive test variability throughout the trial,
TA appeared to have a beneficial effect on several attributes of
Alpha-Lipoic Acid and HIV Scientific
||Studies on lipoate effects on blood redox state
in human immunodeficiency virus infected patients.
Fuchs J, Schofer H, Milbradt R, Freisleben HJ, Buhl R, Siems W,
Department of Dermatology, University Hospital, Frankfurt/Main,
Fed. Rep. of Germany. Arzneimittelforschung. 1993 Dec;43(12):1359-62.
Several investigators have implicated that human immunodeficiency
virus (HIV) infected patients have a compromised antioxidant defense
system. Blood antioxidants are decreased and peroxidation products
of lipids and proteins are increased in the patients. This may have
pathophysiological implications, because antioxidants, such as glutathione,
and reactive oxidants are involved in the regulation of the human
immunodeficiency virus. Consequently it was suggested that HIV infected
patients may benefit from antioxidant supplementation therapy. In
a open and unblinded pilot study the short term effect of the natural
antioxidant lipoate (Thioctacid) on blood antioxidants and peroxidation
products was investigated in HIV positive patients (CDC IV). In
the majority of the patients, lipoate increased plasma ascorbate
(9 of 10 patients) total glutathione (7 of 7 patients), total plasma
thiol groups (8 of 9 patients); T helper lymphocytes and T helper/suppressor
cell ratio (6 of 10 patients), while the lipid peroxidation products
malondialdehyde (8 of 9 patients) and 4-hydroxynonenal (7 of 9 patients)
were decreased. The results of this pilot study indicate that lipoate
supplementation changes the blood redox state of HIV infected patients.
A prospective and longitudinal therapy study is warranted to investigate
the long term effects of lipoate therapy on blood redox state, disease
progression and incidence of opportunistic infections in HIV infected
Acid and protection of the brain Scientific
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.
Alpha-Lipoic Acid and the nervous system Scientific
|| The neurohumoral systems of patients with
ischemic heart disease and under emotional-pain stress: the means
for their pharmacological regulation
Fomichev VI, Pchelintsev VP.
Kardiologiia. 1993;33(10):15-8, 3.
The sympathetic-adrenal and kallikrein-kinin systems were studied
in 225 patients with various coronary heart diseases before and
after therapy with lipoic acid (150 mg/day), tocopherol (100 mg/day),
anaprilin (40 mg/day), prodectin (750 mg/day) or their combination.
Myocardial and adrenal catecholamine levels were measured in experiments
on animals exposed to emotional pain stress. Their levels were found
to be affected by lipoic acid, tocopherol, obsidan or their combinations
in the same doses, taking into account species specificity. Lipoic
acid therapy for patients with coronary heart disease decreased
epinephrine excretion, enhanced the elimination of vanillylmandelic
acid and norepinephrine. Tocopherol lowered daily urinary epinephrine
levels and increased the release of vanillylmandelic acid, without
changing epinephrine excretion. Emotional pain stress resulted in
myocardial epinephrine accumulation and adrenal norepinephrine in
the animals. Lipoic acid prevented this accumulation, whereas tocopherol
did not possess this effect.
Alpha-Lipoic Acid and radiation sickness Scientific
||Radioprotection of hematopoietic tissues in
mice by lipoic acid.
Ramakrishnan N, Wolfe WW, Catravas GN.
Office of the Chair of Science, Armed Forces Radiobiology Research
Institute, Bethesda, Maryland 20889-5145. Radiat Res. 1992 Jun;130(3):360-5.
Lipoic acid is a lipophilic antioxidant that participates in many
enzymatic reactions and is used clinically to treat mushroom poisoning
and metal toxicity. In this report the protective effect of lipoic
acid (oxidized form) against radiation injury to hematopoietic tissues
in mice was assessed by the endogenous and exogenous spleen colony
assays and survival (LD50/30) assay. Intraperitoneal administration
of lipoic acid at a nonlethal concentration of 200 mg/kg body wt,
30 min before irradiation increased the LD50/30 from 8.67 to 10.93
Gy in male CD2F1 mice. Following a 9-Gy irradiation, the yield of
endogenous spleen colony-forming units in mice treated with saline
and lipoic acid was 0.75 +/- 0.5 and 8.9 +/- 1.6, respectively.
Using the exogenous spleen colony assay, lipoic acid treatment increased
the D0 from 0.81 +/- 0.01 to 1.09 +/- 0.01 Gy, yielding a dose modification
factor of 1.34 +/- 0.01. Dihydrolipoic acid (reduced form) has no
radioprotective effect in CD2F1 mice.