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lipoic, lipoic acid, alpha lipoic, alpha-lipoic acid, antioxidant

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 HJ.

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 abstracts
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 nerve conduction.

Alpha-Lipoic Acid and HIV
Scientific abstracts
  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, Grune T.
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 patients.

Alpha-Lipoic Acid and protection of the brain Scientific abstracts


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 abstracts
  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 abstracts
  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.