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PubMed1995

The free radical scavenger, alpha-lipoic acid, protects against cerebral ischemia-reperfusion injury in gerbils.

alpha-Lipoic acid (thioctic acid) was tested for its neuroprotective activity in a Mongolian gerbil model of forebrain ischemia/reperfusion. Adult gerbils were treated for 7 days with two intraperitoneal injections per day of alpha-lipoic acid (20 mg/kg), vehicle or saline and on the 7th day the animals were subjected to 5 min of forebrain ischemia. Ischemic injury was assessed by monitoring the increases in locomotor activity and from the extent of damage to the CA1 hippocampal pyramidal cell layer after 5 days of recovery. By both criteria, alpha-lipoic acid was neuroprotective against ischemia/reperfusion evoked cerebral injury.

Animals↗
PubMed2007

Acrolein, a toxicant in cigarette smoke, causes oxidative damage and mitochondrial dysfunction in RPE cells: protection by (R)-alpha-lipoic acid.

PURPOSE: To understand better the cell and molecular basis for the epidemiologic association between cigarette smoke, oxidant injury, and age-associated macular degeneration, the authors examined the effects of acrolein, a major toxicant in cigarette smoke, on oxidative mitochondrial damage in retinal pigment epithelial (RPE) cells and the reduction of this damage by lipoic acid. METHODS: Cultured human ARPE19 cells and primary cultures of human fetal (hf)RPE were treated with acrolein. The toxicity of acrolein and the protective effects of R-alpha-lipoic acid were examined with a variety of previously described techniques. RESULTS: Acute acrolein exposure exceeding 50 microM (24 hours) in ARPR19 cells caused toxicity, including decreases in cell viability, mitochondrial potential, GSH, antioxidant capacity, Nrf2 expression, enzyme activity (mitochondrial complexes I, II, III; superoxide dismutase; and glutathione peroxidase). Acute exposure also increased oxidant levels, protein carbonyls, and calcium. Continuous acrolein exposure over 8 or 32 days caused similar toxicity but from 10- to 100-fold lower doses (0.1-5 microM). Pretreatment with R-alpha-lipoic acid effectively protected ARPE-19 cells from acrolein toxicity. Primary hfRPE cells were comparable to the ARPE-19 cells in sensitivity to acrolein toxicity and lipoic acid protection. CONCLUSIONS: These results show that acrolein is a mitochondrial toxicant in RPE cells and that acrolein-induced oxidative mitochondrial dysfunction is reduced by lipoic acid. The similar sensitivity of the ARPE-19 and hfRPE cells suggests that both models are useful for studying RPE toxicity and protection. These experiments indicate that mitochondria-targeted antioxidants such as lipoic acid may be an effective strategy for reducing or preventing chronic oxidant-induced RPE degeneration in vivo from a variety of sources, including cigarette smoke.

Acrolein↗
PubMed2003

The influence of lipoic acid on adriamycin induced nephrotoxicity in rats.

Adriamycin, which is widely used in the treatment of various neoplastic conditions, exerts toxic effects in several organs. Adriamycin nephrotoxicity has been recently documented in a variety of animal species. The present study was designed to investigate the effect of lipoic acid on the nephrotoxic potential of adriamycin. The study was carried out with adult male albino rats of Wistar strain. Test animals were divided into four groups of six rats each as follows: Group I (control) received only normal saline throughout the course of the experiment. Group II (ADR) received intravenous injections of adriamycin through the tail vein (1 mg kg(-1) body wt day(-1)) once a week for a period of 12 weeks. Group III (LA) received lipoic acid (35 mg kg(-1) body wt day(-1)) intraperitoneally once a week for a period of 12 weeks. Group IV (ADR + LA) received a single injection of lipoic acid intraperitoneally 24 h prior to the administration of adriamycin through the tail vein once a week for a period of 12 weeks. Intravenous injections of adriamycin resulted in decreased activities of the glycolytic enzymes; hexokinase, phosphoglucoisomerase, aldolase and lactate dehydrogenase in the rat renal tissue. The gluconeogenic enzymes, glucose-6-phosphatase and fructose-1,6-diphosphatase, showed a decline in their activities on adriamycin administration. The transmembrane enzymes namely the Na+,K+-ATPase, Ca2+-ATPase, Mg2+-ATPase and the brush-border enzyme alkaline phosphatase also showed a decrease in their activities. This decrease in the activities of ATPases and alkaline phosphatase suggests basolateral and brush-border membrane damage. Decreased activities of the TCA cycle enzymes isocitrate dehydrogenase, succinate dehydrogenase and malate dehydrogenase, suggest a loss in mitochondrial function and integrity. Nephrotoxicity was evident from the increased excretions of N-acetyl-beta-D-glucosaminidase and gamma-glutamyl transferase in the urine of adriamycin administered rats. These biochemical disturbances were effectively counteracted on pre-treatment with lipoic acid, which brought about an increase in the activities of glycolytic enzymes, ATPases and the TCA cycle enzymes. On the other hand, the gluconeogenic enzymes showed a further decrease in their activities on lipoic acid pretreatment. LA pretreatment also restored the activities of the urinary enzymes to normal. These observations shed light on the nephroprotective action of lipoic acid rendered against experimental aminoglycoside toxicity.

Acetylglucosaminidase↗
PubMed1994

Effect of lipoic acid on cyclophosphamide-induced diabetes and insulitis in non-obese diabetic mice.

In an animal model of type I diabetes, the non-obese diabetic (NOD) mouse, the influence of the antioxidant lipoic acid (LA) on the development of diabetes was investigated. Acceleration of diabetes development with cyclophosphamide (CY) resulted in 60% diabetic animals with severely infiltrated islets within 1-3 weeks. Daily administration of lipoic acid for 20 or 30 days around cyclophosphamide treatment suppressed the incidence of diabetes to 30% (P < 0.05) and 33%, respectively. Semiquantitative analysis of islet infiltration showed a reduction of severe intraislet infiltration and an increase in the percentage of islets with mild per-insular and periductular infiltrates (from 8.4 to 29.6 and 25.9%, respectively, P < 0.01) after lipoic acid treatment. These results show that the protective effect of lipoic acid on diabetes development correlates with partial suppression of islet inflammation. The anti-inflammatory action of lipoic acid may be due to its ability to scavenge oxygen radicals and to suppress nitric oxide production.

Animals↗
PubMed2005

Brain regional responses in antioxidant system to alpha-lipoic acid in arsenic intoxicated rat.

Impaired antioxidant defense mechanisms and oxidative stress are implicated in the pathogenesis of arsenic toxicity. Our study was designed to determine whether alpha-lipoic acid, which has been shown to have substantial antioxidant properties, when administered (70 mg/kg body weight) once daily for 60 days along with arsenic (100 ppm sodium arsenite mixed in drinking water) would prevent arsenic-induced changes in antioxidant defense system, superoxide dismutase (SOD-total SOD, Mn SOD, Cu/Zn SOD), catalase (CAT) and glutathione peroxidase (GSH-PX) in rat brain regions such as cortex, hypothalamus, striatum, cerebellum and hippocampus. The present study also examined the effect of alpha-lipoic acid over arsenic-induced oxidant production and lipid peroxidation level (LPO) in discrete brain regions of rats. The cortex, striatum and hippocampus showed greater decreases in GSH-Px enzyme activity than cerebellum and hypothalamus with arsenic exposure. Striatum had the greatest percentage of decreased activities of total SOD and Mn SOD, whereas cortex had the greatest percentage decrease in the activity of Cu/Zn SOD in arsenic-alone treated rats. Hypothalamus and cerebellum exhibited the lowest catalase activity among all tested regions in arsenic-only treated rats. Rate of dichlorofluorescin oxidation, an indication of reactive oxygen species and other intracellular oxidants production was increased with arsenic exposure in all brain regions studied. Cortex, hippocampus and striatum exhibited greater increase of LPO levels than cerebellum and hypothalamus. SOD, CAT, GSH-Px activities were upregulated in arsenic plus lipoic acid treated versus arsenic-only treated rats. Also, simultaneous lipoic acid treatment along with arsenic proved to be sufficient in reducing oxidant production and LPO level in all rat brain regions. Our results demonstrate that arsenic-induced deficits in antioxidant enzyme activities and increase in oxidant production and lipid peroxidation level in brain regions can be overcome through simultaneous treatment with lipoic acid.

Animals↗
PubMed2006

Decrease in NADPH-cytochrome P450 reductase activity of the human heart, Liver and lungs in the presence of alpha-lipoic acid.

BACKGROUND: NADPH-cytochrome P450 reductase (CPR) is the electron donor protein for several oxygenase enzymes located in the endoplasmic reticulum. These oxygenases include P450 family enzymes involved in the metabolism of endogenous and exogenous substances. The enzyme is involved in adriamycin (anticancer drug) and paraquat (herbicide) toxicity. CPR is a flavoprotein containing both flavine-adenine dinucleotide and flavine mononucleotide. A structural study showed the presence of several sulfhydryl (SH) groups in the CPR molecule. Some of them play a key role in catalytic activity. As alpha-lipoic acid contains a disulfide bond, it may react with the SH group of CPR. The aim of the study was to evaluate the effect of alpha-lipoic acid on human P450 reductase activity. METHODS: The activity of the enzyme was determined by measuring the rate of cytochrome c reduction at 550 nm, in vitro, using heart, liver and lung microsomes. RESULTS: The activity of CPR was decreased in all organs after addition of alpha-lipoic acid to the reaction mixture at concentrations of 0.01, 0.10 and 1.00 mM. The decreases in CPR activity were concentration-dependent and the sequence of relative inhibition was as follows: heart >lung >liver. However, the statistical significance of CPR activity vs. control was observed in the heart in the presence of 1.00 mM alpha-lipoic acid and in the lung at 0.10 and 1.00 mM alpha-lipoic acid. CONCLUSION: alpha-Lipoic acid decreased NADPH-CPR activity in the lung and heart. The present results are promising for future studies to obtain the most effective antidote for adriamycin and paraquat toxicity.

Adult↗
PubMed1995

Determination of lipoic acid in human plasma by high-performance liquid chromatography with electrochemical detection.

A selective and sensitive method for the determination of lipoic acid in human plasma samples has been developed. After enzymatic hydrolysis of the sample, the liberated lipoic acid was extracted by a solid-phase cartridge and measured by HPLC using electrochemical detection. The detection limit was 1 ng/ml lipoic acid in plasma. The calibration curve was non-linear in the range 0.01-50 microgram/ml but could be described by a power function. The average extraction recoveries were 82.5 and 85.1% at the 25 and 2500 ng/ml levels, respectively. Coefficients of variation for both within-day and day-to-day analysis were between 2.1 and 9.4%. The assay method is sensitive, reproducible and suitable for disposition studies of lipoic acid in humans.

Chromatography, High Pressure Liquid↗
PubMed1993

Analysis of lipoic acid in biological samples by gas chromatography with flame photometric detection.

A selective and sensitive gas chromatographic method for the analysis of lipoic acid in biological samples has been developed. After base hydrolysis of the sample, the liberated lipoic acid was converted into its S,S-diethoxycarbonyl methyl ester derivative and measured by gas chromatography using a DB-210 capillary column and a flame photometric detector. The calibration curve was linear in the range 20-500 ng, and the detection limit was ca. 50 pg injected. The best hydrolysis conditions for the biological samples were obtained by using 2 M potassium hydroxide containing 4% bovine serum albumin at 110 degrees C for 3 h. Using this method, lipoic acid in the hydrolysate could be selectively determined without any interference from matrix substances. Analytical results for the determination of lipoic acid in the mouse tissue and bacterial cell samples are presented.

Animals↗
PubMed1997

Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells.

Depletion of cellular antioxidant defense mechanisms and the generation of oxygen free radicals by advanced glycation end products (AGEs) have been proposed to play a major role in the pathogenesis of diabetic vascular complications. Here we demonstrate that incubation of cultured bovine aortic endothelial cells (BAECs) with AGE albumin (500 nmol/l) resulted in the impairment of reduced glutathione (GSH) and ascorbic acid levels. As a consequence, increased cellular oxidative stress led to the activation of the transcription factor NF-kappaB and thus promoted the upregulation of various NF-kappaB-controlled genes, including endothelial tissue factor. Supplementation of the cellular antioxidative defense with the natural occurring antioxidant alpha-lipoic acid before AGE albumin induction completely prevented the AGE albumin-dependent depletion of reduced glutathione and ascorbic acid. Electrophoretic mobility shift assays (EMSAs) revealed that AGE albumin-mediated NF-kappaB activation was also reduced in a time- and dose-dependent manner as long as alpha-lipoic acid was added at least 30 min before AGE albumin stimulation. Inhibition was not due to physical interactions with protein DNA binding, since alpha-lipoic acid, directly included into the binding reaction, did not prevent binding activity of recombinant NF-kappaB. Western blots further demonstrated that alpha-lipoic acid inhibited the release and translocation of NF-kappaB from the cytoplasm into the nucleus. As a consequence, alpha-lipoic acid reduced AGE albumin-induced NF-kappaB mediated transcription and expression of endothelial genes relevant in diabetes, such as tissue factor and endothelin-1. Thus, supplementation of cellular antioxidative defense mechanisms by extracellularly administered alpha-lipoic acid reduces AGE albumin-induced endothelial dysfunction in vitro.

Antioxidants↗
PubMed1991

Effect of DL alpha-lipoic acid on some carbohydrate metabolising enzymes in stone forming rats.

DL alpha-lipoic acid has been shown to prevent the induced precipitation of calcium oxalate crystals in the renal tissues of laboratory animals. The acid seems to have a profound influence on carbohydrate metabolism in diabetic rats. Here the effect of alpha-lipoic acid was studied on certain key carbohydrate metabolising enzymes in the tissues of calcium oxalate stone forming rats administered with glycollate as oxalate precursor. There was augmentation of glycolysis in the renal tissues of stone forming as well as lipoate administered rats. The two major gluconeogenic enzymes, glucose-6-phosphatase (G6P) and fructose-1, 6 diphosphatase (FDP) were significantly inhibited in tissues of calculogenic rats. Lipoic acid also reduced the enzyme activities significantly. The citric acid cycle enzymes were not influenced to an appreciable extent. The observed alterations are likely to be due to the regulatory effects of oxalate and lipoate on the enzyme systems.

Animals↗
PubMed1995

Reversible inhibition of NADPH-cytochrome P450 reductase by alpha-lipoic acid.

NADPH-cytochrome-P450 reductase both purified from rat hepatic microsomes and involved in microsomal fraction was inactivated by treatment with alpha-lipoic acid. Since alpha-lipoic acid contains disulfide bond, it reacts with SH-groups of the reductase via the reaction of thiol-disulfide exchange resulting in the loss of the enzyme reducing activity. NADP+ completely protected reductase from the inactivation. The modification of reductase was reversible: the modified enzyme was partially reactivated with dithiothreitol and dihydrolipoic acid in the case when cytochrome c was used as a substrate of reductase. In the case when inorganic substrate, K3Fe(CN)6, was used for assay the activity of modified reductase no reactivation was observed. It was found that the order of the reaction of inactivation of membrane-bound microsomal reductase is equal to 1.2 +/- 0.2, which is in an agreement with pseudo-first order kinetics, and the second-order-rate constant of 26 M-1min-1. The results have shown that well known therapeutic agent alpha-lipoic acid is an efficient inhibitor of both purified and microsomal reductase.

Animals↗
PubMed2003

Lipoic acid supplementation prevents angiotensin II-induced renal injury.

BACKGROUND: Angiotensin II (Ang II)-induced renal injury is associated with perivascular inflammation, cell proliferation, and increased superoxide production in the vascular wall. We tested whether lipoic acid, an endogenous antioxidant, protects against the Ang II-induced inflammatory response and end-organ damage. METHODS: Light microscopy, immunohistochemistry, electrophoretic mobility shift assay, Northern blots, and high-pressure liquid chromatography (HPLC) were used in kidneys from double transgenic rats (dTGR) harboring human renin and angiotensinogen genes and normotensive Sprague Dawley (SD) rats. The effects of lipoic acid supplementation for three weeks were examined in dTGR and SD rats. RESULTS: Lipoic acid effectively prevented Ang II-induced glomerular and vascular damage in the kidneys and completely prevented the development of albuminuria. Ang II-induced leukocyte infiltration and cell proliferation in the kidney were attenuated. The redox-sensitive transcription factors nuclear factor (kappa) B (NF-kappa B) and activator protein-1 (AP-1) in the kidneys were increased in dTGR compared with SD, and were effectively reduced. Renal glutathione levels were much higher in dTGR than in SD, while the opposite was true for cysteine levels. These results suggested increased renal glutathione oxidation in dTGR, leading to cysteine shortage. Lipoic acid partly prevented renal cysteine depletion and increased hepatic cysteine and glutathione concentrations. This effect was accompanied by increased hepatic gamma-glutamylcysteine synthetase mRNA expression. CONCLUSION: Our in vivo results suggest that lipoic acid protects against Ang II-induced renal injury through anti-inflammatory/antioxidative mechanisms. The effects are associated with decreased NF-kappa B and AP-1 activation, as well as improved thiol homeostasis.

Albuminuria↗
PubMed1997

Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy.

Antioxidant treatment has been shown to prevent nerve dysfunction in experimental diabetes, providing a rationale for a potential therapeutic value in diabetic patients. The effects of the antioxidant alpha-lipoic acid (thioctic acid) were studied in two multicenter, randomized, double-blind placebo-controlled trials. In the Alpha-Lipoic Acid in Diabetic Neuropathy Study, 328 patients with NIDDM and symptomatic peripheral neuropathy were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (ALA 1,200 mg; 600 mg; 100 mg) or placebo (PLAC) over 3 weeks. The total symptom score (TSS) (pain, burning, paresthesia, and numbness) in the feet decreased significantly from baseline to day 19 in ALA 1,200 and ALA 600 vs. PLAC. Each of the four individual symptom scores was significantly lower in ALA 600 than in PLAC after 19 days (all P < 0.05). The total scale of the Hamburg Pain Adjective List (HPAL) was significantly reduced in ALA 1,200 and ALA 600 compared with PLAC after 19 days (both P < 0.05). In the Deutsche Kardiale Autonome Neuropathie Studie, patients with NIDDM and cardiac autonomic neuropathy diagnosed by reduced heart rate variability were randomly assigned to treatment with a daily oral dose of 800 mg alpha-lipoic acid (ALA) (n = 39) or placebo (n = 34) for 4 months. Two out of four parameters of heart rate variability at rest were significantly improved in ALA compared with placebo. A trend toward a favorable effect of ALA was noted for the remaining two indexes. In both studies, no significant adverse events were observed. In conclusion, intravenous treatment with alpha-lipoic acid (600 mg/day) over 3 weeks is safe and effective in reducing symptoms of diabetic peripheral neuropathy, and oral treatment with 800 mg/day for 4 months may improve cardiac autonomic dysfunction in NIDDM.

Antioxidants↗
PubMed1982

[Characteristics of 35S-lipoic acid absorption by the blood cells in breast cancer].

The peculiar characteristics of 35S lipoic acid uptake by blood red cells in breast cancer patients were studied. The rate of 35S lipoic acid uptake by red cells in cancer patients was much higher than that in healthy female donors. The difference was less significant in cases of acute mastitis or benign tumors. The increased uptake of 35S lipoic acid by red cells may prove instrumental in the diagnosis and, probably, therapy of breast cancer.

Absorption↗
PubMed2005

Endogenous production of lipoic acid is essential for mouse development.

alpha-Lipoic acid (LA) is a cofactor for mitochondrial alpha-ketoacid dehydrogenase complexes and is one of the most potent, natural antioxidants. Reduction of oxidative stress by LA supplementation has been demonstrated in patients with diabetic neuropathy and in animal models. To determine how normal development or pathological conditions are affected by genetic alterations in the ability of mammalian cells to synthesize LA and whether dietary LA can circumvent its endogenous absence, we have generated mice deficient in lipoic acid synthase (Lias). Mice heterozygous for disruption of the Lias gene develop normally, and their plasma levels of thiobarbituric acid-reactive substances do not differ from those of wild-type mice. However, the heterozygotes have significantly reduced erythrocyte glutathione levels, indicating that their endogenous antioxidant capacity is lower than those of wild-type mice. Homozygous embryos lacking Lias appear healthy at the blastocyst stage, but their development is retarded globally by 7.5 days postcoitum (dpc), and all the null embryos die before 9.5 dpc. Supplementing the diet of heterozygous mothers with LA (1.65 g/kg of body weight) during pregnancy fails to prevent the prenatal deaths of homozygous embryos. Thus, endogenous LA synthesis is essential for developmental survival and cannot be replaced by LA in maternal tissues and blood.

Animals↗
PubMed2003

Protective effect of lipoic acid on adriamycin induced lipid peroxidation in rat kidney.

Adriamycin, which is widely used in the treatment of various neoplastic conditions, exerts toxic effects in many organs. The present study was designed to investigate the effect of lipoic acid upon adriamycin induced peroxidative damages in rat kidney. The increase in peroxidated lipids on adriamycin administration was accompanied by alterations in the antioxidant defense systems. The extent of nephrotoxicity induced by adriamycin was evident from the decreased activities of the enzymes gamma-glutamyl transferase and beta-glucuronidase in the rat renal tissues. The study was carried out with adult male albino rats of Wistar strain, which comprised of one control and three experimental groups. Group I rats served as controls. Group II rats received adriamycin (1 mg kg(-1) body wt day(-1)) intravenously through the tail vein. Group III rats were given lipoic acid (35 mg kg(-1) body wt day(-1)) intraperitoneally. Group IV rats were given lipoic acid 24 h before the administration of adriamycin. Rats subjected to adriamycin administration showed a decline in the thiol capacity of the cell accompanied by high malondialdehyde levels along with lowered activities of catalase, superoxide dismutase, glutathione peroxidase and glutathione metabolizing enzymes (glutathione reductase, glucose-6-phosphate dehydrogenase, glutathione-S-transferase). Lipoic acid pretreatment also restored the activities of gamma-glutamyl transferase and beta-glucuronidase nearly to control levels thereby suggesting nephroprotection. The study has highlighted the beneficial effects of lipoic acid pretreatment in reversing the damages caused by adriamycin and thereby bringing about an improvement in the oxidative stress parameters.

Animals↗
PubMed1999

Protective role of DL-alpha-lipoic acid against mercury-induced neural lipid peroxidation.

Experimental neurotoxicity in rat models was induced by an intramuscular injection of mercuric chloride. dl-alpha-lipoic acid was administered as an antidote in three protocols of experimental design. Two protocols of short-term exposure of mercury was designed, one with prophylactic therapy and the other with curative therapy of lipoic acid. The third protocol was with prophylactic therapy of lipoic acid on long-term exposure of mercury. Enhanced lipid peroxidation, depleted non-enzymic and perturbed enzymic antioxidant status were observed in cerebral cortex, cerebellum and sciatic nerves of the toxic groups. The ameliorating effect of lipoic acid and its therapeutic efficacy during various modes of therapy, on the antioxidant status was established in the nervous tissues.

Animals↗
PubMed1998

Determination of lipoic acid by precolumn derivatization with monobromobimane and reversed-phase high-performance liquid chromatography.

A new method for the quantitation of lipoic acid in plasma and tissues based on the selective precolumn derivatization of thiols with the fluorescent label monobromobimane is described. After extraction with diethyl ether, the dithiolane ring of lipoic acid is opened by reduction with NaBH4 before the free thiols can react with the label. Separation and quantitation was achieved by reversed-phase HPLC and fluorescence detection. The concentration-response curve was linear from 20 to 3000 nM in plasma. The recovery as determined with [3H]lipoic acid was 60.9% from plasma and 61.4% from rat heart tissue. The pretreatment of samples with N-ethylmaleimide makes it possible to differentiate between reduced and oxidized forms of lipoic acid.

Animals↗