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PubMed1988

Interplay between lipoic acid and glutathione in the protection against microsomal lipid peroxidation.

Reduced glutathione (GSH) delays microsomal lipid peroxidation via the reduction of vitamin E radicals, which is catalyzed by a free radical reductase (Haenen, G.R.M.M. et al. (1987) Arch. Biochem. Biophys. 259, 449-456). Lipoic acid exerts its therapeutic effect in pathologies in which free radicals are involved. We investigated the interplay between lipoic acid and glutathione in microsomal Fe2+ (10 microM)/ascorbate (0.2 mM)-induced lipid peroxidation. Neither reduced nor oxidized lipoic acid (0.5 mM) displayed protection against microsomal lipid peroxidation, measured as thiobarbituric acid-reactive material. Reduced lipoic acid even had a pro-oxidant activity, which is probably due to reduction of Fe3+. Notably, protection against lipid peroxidation was afforded by the combination of oxidized glutathione (GSSG) and reduced lipoic acid. It is shown that this effect can be ascribed completely to reduction of GSSG to GSH by reduced lipoic acid. This may provide a rationale for the therapeutic effectiveness of lipoic acid.

Animals↗
PubMed1999

Lipoic acid prevention of neural tube defects in offspring of rats with streptozocin-induced diabetes.

OBJECTIVE: Increased oxidant stress has been suggested to play a role in the pathogenesis of disturbed embryogenesis in diabetic pregnancies. The present study was conducted to determine whether administration of lipoic acid, a naturally occurring antioxidant, would reduce the incidence of diabetic embryopathy in the streptozocin-induced diabetic rat model. STUDY DESIGN: After conception, rats were randomly distributed to 5 groups. From day 1, rats were daily injected intraperitoneally with either lipoic acid, 30 mg/kg, or vehicle. At day 6, rats from groups 3, 4, and 5 were made diabetic by a single intraperitoneal injection of streptozocin. Group 4 rats were injected with lipoic acid from day 1 to day 6, after vehicle treatment until day 17. At day 17 of gestation, rats were killed. The fetuses were released from the yolk sacs and surrounding decidua and were examined for size, resorption rate, and neural tube defects. RESULTS: Pregnant diabetic rats treated with vehicle lost weight during pregnancy (-3.2 +/- 1.9 g/d), as opposed to normal pregnancy-related weight gain (3.5 +/- 0.5 g/d). Treatment with lipoic acid protected against diabetes-induced weight loss, without a measurable effect on fed-state glucose concentrations. Daily treatment with lipoic acid (pregnancy days 1 to 17) was efficient in reducing the resorption rate from 24.0% +/- 9.5% in vehicle-treated diabetic rats to 10.2% +/- 4.8% in lipoic acid-treated diabetic rats (P <.05). The rate of neural tube defects in diabetic rats treated with lipoic acid throughout the pregnancy was reduced from 26.0% +/- 7.0% to 10.2% +/- 3.2% (P <.05). In rats treated only during pregnancy days 1 to 5 (before diabetes induction), lipoic acid failed to exert its protective effects against neural tube defects, which emphasizes the importance of the presence of lipoic acid during the organogenesis period. The atherosis of placental vasculature demonstrated in the vehicle-treated diabetic rats was absent from placentas obtained from lipoic acid-treated diabetic animals. CONCLUSIONS: Our data demonstrate a protective effect of lipoic acid against diabetic embryopathy, fetal losses, and ultrastructural alteration of diabetic placentas.

Animals↗
PubMed1999

alpha-Lipoic acid decreases oxidative stress even in diabetic patients with poor glycemic control and albuminuria.

In the present cross-sectional study, the influence of alpha-lipoic acid on markers of oxidative stress, assessed by measurement of plasma lipid hydroperoxides (ROOHs), and on the balance between oxidative stress and antioxidant defence, determined by the ratio ROOH/(alpha-tocopherol/cholesterol), was examined in 107 patients with diabetes mellitus. Patients receiving alpha-lipoic acid (600 mg/day for > 3 months) had significant lower ROOHs and a lower ROOH/(alpha-tocopherol/cholesterol) ratio than those without alpha-lipoic acid treatment [ROOH: 4.76 +/- 2.49 vs. 7.16 +/- 3.22 mumol/l; p < .0001] and [ROOH/(alpha-tocopherol/cholesterol): 1.37 +/- 0.72 vs. 2.16 +/- 1.17; p < 0.0001]. In addition, the influence of glycemic control and albuminuria on ROOHs and on the ratio of ROOH/(alpha-tocopherol/cholesterol) was examined in the presence and absence of alpha-lipoic acid treatment. Patients were subdivided into three groups based on (1) their HbA1 levels (< 7.5, 7.5-9.5, and > 9.5%) and (2) their urinary albumin concentrations (< 20, 20-200, and > 200 mg/l). Neither poor glycemic control, nor the presence of micro- or macroalbuminuria prevented the antioxidant effect of alpha-lipoic acid. Using stepwise multiple regression analysis, alpha-lipoic acid was found to be the only factor significantly predicting low ROOHs and a low ratio of ROOH/(alpha-tocopherol/cholesterol). These data provide evidence that treatment with alpha-lipoic acid improves significantly the imbalance between increased oxidative stress and depleted antioxidant defence even in patients with poor glycemic control and albuminuria.

Albuminuria↗
PubMed1991

Alpha-lipoic acid is an effective inhibitor of human immuno-deficiency virus (HIV-1) replication.

Alpha-lipoic acid, a naturally occurring disulfide-compound that acts as a cellular coenzyme, inhibits replication of HIV-1 in cultured lymphoid T-cells. Alpha-lipoic acid was added 16 hours after infection of the T-cell lines Jurkat, SupT1 and Molt-4 with HTLV IIIB and HIV-1 Wal (a wild type HIV-1 isolate). We observed a dose dependent inhibition of HIV-1-replication in CPE (Cytopathic effect) formation, reverse transcriptase activity and plaque formation on CD4-transformed HeLa-cells. An over 90% reduction of reverse transcriptase activity could be achieved with 70 micrograms alpha-lipoic acid/ml, a complete reduction of plaque-forming units at concentrations of greater than or equal to 35 micrograms alpha-lipoic acid/ml. An augmentation of the antiviral activity was seen by combination of zidovudine and low dose of alpha-lipoic acid (7 micrograms/ml). Trypan blue staining revealed no toxic effects of alpha-lipoic acids on peripheral blood mono-nuclear cells and T-cell lines even in concentrations of greater than or equal to 70 micrograms/ml. Therefore, we propose the inclusion of alpha-lipoic acid into chemotherapy trials in combination with zidovudine.

Cells, Cultured↗
PubMed2002

Inhibition of LPS-induced nitric oxide and TNF-alpha production by alpha-lipoic acid in rat Kupffer cells and in RAW 264.7 murine macrophages.

The activation of Kupffer cells represents a central mechanism of inflammatory liver injury involving the production of two important inflammatory mediators, nitric oxide and TNF-alpha. The aim of this study was to investigate the effect of the hepatoprotective compound alpha-lipoic acid (thioctic acid) on the production of nitric oxide and TNF-alpha in isolated rat Kupffer cells and RAW 264.7 macrophages. Isolated rat Kupffer cells or RAW 264.7 were either untreated, treated with alpha-lipoic acid (500 micro g/mL), or activated with 1 micro g/mL of lipopolysaccharide in the presence or absence of alpha-lipoic acid (0.2-500 micro g/mL). After 20 h the accumulation of nitrite was measured by the Griess assay. Tumour necrosis factor-alpha secretion was quantified after 4 h by L929 bioassay. Cell viability was determined by mitochondrial reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) DNA binding activity by gelshift assays. Treatment of Kupffer cells and RAW 264.7 with alpha-lipoic acid alone had no effect on basal nitric oxide production. However, alpha-lipoic acid significantly inhibited lipopolysaccharide-induced nitrite accumulation. alpha-Lipoic acid did not alter basal TNF-alpha secretion in Kupffer cells, whereas it significantly inhibited lipopolysaccharide-induced TNF-alpha production. alpha-Lipoic acid attenuated the activation of nuclear factor-kappaB and AP-1, two transcription factors pivotal in induction of inducible nitric oxide synthase and TNF-alpha. alpha-Lipoic acid significantly inhibits lipopolysaccharide-induced macrophage production of nitric oxide and TNF-alpha via an attenuated activation of NF-kappaB and activator protein-1. The reduced production of nitric oxide and TNF-alpha in Kupffer cells may be involved in the hepatoprotective action conveyed by alpha-lipoic acid.

Animals↗
PubMed2004

Burning mouth syndrome: the efficacy of lipoic acid on subgroups.

OBJECTIVE: We have examined the effect of alpha-lipoic acid (ALA, tioctic acid; Tiobec), a free radical scavenger, on the discomfort of burning mouth syndrome (BMS) in patients who had used tranquillizers previously, compared with those who had not. METHODS: In this study we gave lipoic acid for 2 months to two groups of 20 BMS patients, one of which had previously been treated with tranquillizers. RESULTS: The results showed greater effectiveness of lipoic acid in BMS patients who had not previously used tranquillizers. CONCLUSIONS: The patients with BMS who had previously been treated with tranquillizers responded poorly to therapy with lipoic acid compared with those who had not received previous psychotropic therapy.

Adult↗
PubMedDate not supplied

Effect of DL alpha-lipoic acid on tissue lipid peroxidation and antioxidant systems in normal and glycollate treated rats.

The cytoprotective activity of alpha-lipoic acid against free radical toxicity, manifested during experimental hyperoxaluria, has been investigated. Glycollate was used as the inducer of oxalate hyperoxaluria in rats. The increase in lipid peroxidation and superoxide dismutase (SOD) activity, associated with a decrease in catalase activity and glutathione (GSH) level, are the salient features observed in tissues of hyperoxaluric rats. Free radical toxicity in the glycollate fed rats is effectively counteracted by lipoic acid administration. Lipoic acid administration brought about a significant decrease in peroxidative levels with an increase in catalase activity and glutathione level. These observations highlight the antioxidant property of alpha-lipoic acid and its cytoprotective action against experimental hyperoxaluria.

Animals↗
PubMed2000

Effect of dl-alpha-lipoic acid on the status of lipid peroxidation and antioxidants in aged rats.

The effect of dl-alpha-lipoic acid on lipid peroxidation and antioxidants status has been studied in the blood of young and aged rats. dl-alpha-lipoic acid, an antioxidant, was administered intraperitoneally for 7 and 14 days. Enzymatic and non-enzymatic antioxidant levels decreased with age but this decrease was attenuated by dl-alpha-lipoic acid. Lipid peroxide levels increased with age, and were decreased by lipoic acid administration. These results suggest that biochemical lesions which are considered to be part of the normal ageing process are neutralized by dl-alpha-lipoic acid.

Aging↗
PubMed1994

Alpha-lipoic acid reduction by mammalian cells to the dithiol form, and release into the culture medium.

Lipoic acid has been reported recently to be an effective antioxidant in biological systems. It may act in vivo through reduction to its dithiol form, dihydrolipoic acid. Using a dual Hg/Au electrode, and HPLC with electrochemical detection, a method was developed which allowed simultaneous measurement of lipoic acid and dihydrolipoic acid, at nanomolar levels. (RS)-alpha-Lipoic acid was added to human cells in tissue culture (Jurkat T-lymphocytes and primary neonatal diploid fibroblasts). Lipoic acid was converted rapidly by the cells to dihydrolipoic acid, which accumulated in the cell pellet. Monitored over a 2-hr interval, dihydrolipoic acid was released, and several-fold more dihydrolipoic acid could be found in the medium than in the pellet.

Chromatography, High Pressure Liquid↗
PubMed1980

[An electrochemical evidence that some hormones influence the transmembrane transport of lipoic acid by Escherichio coli K 12 (author's transl)].

The influence of diverse substances on the transmembrane transport of lipoic acid can be followed by a recently developed method based on electrochemical measurements of the oxydo-reduction of lipolic acid. This technique was applied to study some hormonal effects on E. coli. The results show that the active transport of lipoic acid (at low lipoic acid concentration) through the E. coli K 12 membrane is increased by hydrocortisone and insulin, but remains unaffected by adrenalin. At high lipoic acid concentration, its passive diffusion through the E. coli membrane is enhanced by adrenalin, but decreased by insulin and hydrocortisone. These results are similar to those reported for rat liver mitochondria and erythrocites.

Cell Membrane Permeability↗
PubMed2000

Effect of alpha-lipoic acid supplementation on oxidative protein damage in the streptozotocin-diabetic rat.

An increase in oxidative stress may contribute to the development of oxidative protein damage in streptozotocin diabetic rats. In the present study, the influence of alpha-lipoic acid supplementation on plasma protein carbonyl, plasma thiol, and plasma lipid hydroperoxide levels was examined in order to characterize the relationship between the oxidative stress and the oxidative protein damage. Rats were randomly divided into three groups of equal body weight. Chronic hyperglycemia was induced by intravenous streptozotocin injection in both the group of male Wistar rats to be supplemented with alpha-lipoic acid and the group that was not to receive alpha-lipoic acid. Nondiabetic rats formed the control group and received a saline injection. In streptozotocin diabetic rats with and without alpha-lipoic acid supplementation, plasma carbonyl levels were significantly increased, while plasma thiol levels were significantly decreased compared with those of the control group. Plasma lipid hydroperoxide levels were significantly increased in diabetic rats without alpha-lipoic acid supplementation compared with those of the controls, but the lipid hydroperoxide levels in the alpha-lipoic acid supplemented group were no different from those of the controls. In streptozotocin-diabetic rats, oxidative stress was significantly decreased in the alpha-lipoic acid-supplemented group. The results of this study suggest that alpha-lipoic acid, by decreasing oxidative stress, may be effective in preventing oxidative protein damage, which may contribute to the development of diabetic complications.

Analysis of Variance↗
PubMed1999

Lipoic acid prevents development of the hyperdynamic circulation in anesthetized rats with biliary cirrhosis.

Chronic bile duct ligation is associated with the development of oxidant injury, biliary cirrhosis, portal hypertension, and a hyperdynamic circulation. We have previously demonstrated that the hyperdynamic circulation in the partial portal vein-ligated rat can be prevented by the administration of N-acetylcysteine. To extend these findings, we have examined the effect of lipoic acid, a thiol-containing antioxidant, on hemodynamics, oxidative stress, and nitric oxide (NO) production in bile duct-ligated (BDL) cirrhotic rats. Lipoic acid was given continuously in drinking water to normal and BDL rats; control rats received ordinary drinking water, and animals were studied at 24 days following surgery. Lipoic acid prevented the development of the hyperdynamic circulation (cardiac index [CI]: 15.7 +/- 2.0 vs. 29.5 +/- 2.1 mL x min-1 x 100 g-1; P <. 05) and significantly attenuated the rise in portal pressure (PP) (12.7 +/- 0.8 vs. 15.2 +/- 0.5 mm Hg; P <.05). Hepatic nitric oxide synthase (NOS) activity and plasma nitrite/nitrate concentration increased significantly following bile duct ligation, and both of these were prevented by lipoic acid. Lipoic acid had no effect on the biochemical or histological parameters of liver function in the cirrhotic group. We conclude that lipoic acid prevents the development of the hyperdynamic circulation in the rat model of biliary cirrhosis, and that this is associated with decreased synthesis of NO.

Animals↗
PubMed2006

Vitamin E and alpha-lipoic acid supplementation increase bleeding tendency via an intrinsic coagulation pathway.

Vitamin E and alpha-lipoic acid are potent nutritional antioxidants, and when used together, their antioxidant capabilities are improved as alpha-lipoic acid recycles vitamin E. Supplementation of vitamin E has been shown to prolong platelet aggregation but the effects of vitamin E and alpha-lipoic acid supplementation on bleeding tendency have yet to be reported. Young, male rats consumed either control diet (n=5) or vitamin E and alpha-lipoic acid-supplemented diet (n=5) for 14 weeks. Activated partial thromboplastin time (APTT) and prothrombin time (PT) were measured as markers of intrinsic and extrinsic coagulation pathways respectively in addition to lipid peroxidation (malondialdehyde). Supplementation significantly prolonged APTT (23.8+/-1.5 vs 31.4+/-1.2s, p<0.05) compared to the control diet; however, there was no significant difference in PT (27.8+/-1.5 vs 26.6+/-0.9s, p>0.05). While vitamin E was increased (p<0.05), there was no significant difference in plasma levels of malondialdehyde (p>0.05). Dietary supplementation of vitamin E and alpha-lipoic acid increases bleeding tendency via inhibition of the intrinsic coagulation pathway with no change in markers of lipid peroxidation. Such supplementation could benefit patients with cardiovascular disease who exhibit elevated levels of coagulation and oxidative stress.

Animals↗
PubMedDate not supplied

Effects of lipoic acid in hexacarbon-induced neuropathy.

The effects of lipoic acid on hexacarbon neurotoxicity in rats were investigated. Rats were exposed by inhalation to n-hexane for 24 hours/day, 7 days/week, up to a total period of 9 weeks. Eight animals were exposed to 700 ppm n-hexane only, and eight animals were exposed to 700 ppm n-hexane and additionally received 100 mumol/kg lipoic acid PO daily. Clinical status of the animals was evaluated by examination of general condition, motor performance tests and neurophysiological measurements of caudal nerve motor conduction velocity. Results showed that animals exposed to 700 ppm n-hexane developed severe motor neuropathy leading to paralysis by the 6th week. Motor distal latencies of these animals were severely prolonged. In contrast, in animals treated with lipoic acid the onset of motor neuropathy was delayed for approximately 3 weeks as could be demonstrated by motor performance tests and measurements of motor distal latencies.

Action Potentials↗
PubMed1998

Investigations on the pharmacokinetics of alpha-lipoic acid in healthy volunteers.

AIM: The aim of the present study was to examine the pharmacokinetics of racemic alpha-lipoic acid in twelve healthy volunteers following single oral administration of 200 and 600 mg (Thioctacid 200 film tablets). SUBJECTS, MATERIAL AND METHODS: Each film tablet contained 200 mg of alpha-lipoic acid. In addition, an injection solution containing 200 mg of alpha-lipoic acid was administered. Plasma concentrations of alpha-lipoic acid were determined using a validated reversed-phase HPLC method with electrochemical detection having a lower limit of quantitation of 1 ng/ml. The areas under curve (AUC) were 46.82 +/- 21.46 and 157.97 +/- 35.05 microg x min/ml for the oral and intravenous administration of 200 mg, respectively. RESULTS: The AUC following oral administration of 600 mg was 157.83 +/- 35.82 microg x min/ml. The difference in mean t(1/2) for the two oral doses and the i.v. dose (in the range of 25.3-32.7 min) was not statistically significant. CONCLUSION: The lack of a significant difference between values for apparent total plasma clearance for the 200 and 600 mg doses indicates non-saturable kinetics of alpha-lipoic acid in healthy volunteers in this dose range. The absolute bioavailability after the 200 mg dose was 29.1 +/- 10.3%.

Administration, Oral↗
PubMed2001

Effect of alpha-lipoic acid on the progression of endothelial cell damage and albuminuria in patients with diabetes mellitus: an exploratory study.

Oxidative stress plays a central role in the pathogenesis and progression of late microangiopathic complications (diabetic nephropathy) in diabetes mellitus. Previous studies suggested that treatment of diabetic patients with the antioxidant alpha-lipoic acid reduce oxidative stress and urinary albumin excretion. In this prospective, open and non-randomized study, the effect of alpha-lipoic acid on the progression of endothelial cell damage and the course of diabetic nephropathy, as assessed by measurement of plasma thrombomodulin and urinary albumin concentration (UAC), was evaluated in 84 patients with diabetes mellitus over 18 months. Forty-nine patients (34 with Type 1 diabetes, 15 with Type 2 diabetes) had no antioxidant treatment and served as a control group. Thirty-five patients (20 with Type 1 diabetes, 15 with Type 2 diabetes) were treated with 600 mg alpha-lipoic acid per day. Only patients with an urinary albumin concentration <200 mg/l were included into the study. After 18 months of follow up, the plasma thrombomodulin level increased from 35.9+/-9.5 to 39.7+/-9.9 ng/ml (P<0.05) in the control group. In the alpha-lipoic acid treated group the plasma thrombomodulin level decreased from 37.5+/-16.2 to 30.9+/-14.5 ng/ml (P<0.01). The UAC increased in patients without alpha-lipoic acid treatment from 21.2+/-29.5 to 36.9+/-60.6 ng/l (P<0.05), but was unchanged with alpha-lipoic acid. It is postulated that the significant decrease in plasma thrombomodulin and failure of UAC to increase observed in the alpha-lipoic acid treated group is due to antioxidative effects of alpha-lipoic acid, and if so that oxidative stress plays a central role in the pathogenesis of diabetic nephropathy. Furthermore, progression of the disease might be inhibited by antioxidant drugs. A placebo-controlled study is needed.

Albuminuria↗
PubMed2004

Protective effect of DL-alpha-lipoic acid in cyclophosphamide induced oxidative injury in rat testis.

The aim of the present study was to evaluate the protective effect of DL-alpha-lipoic acid on the biochemical changes, tissue peroxidative damage and abnormal antioxidant levels in the rat testis during cyclophosphamide (CP)-induced injury. Adult male Wistar rats were divided into four treatment groups: (I) control, (II) 15 mg/kg CP once a week for 10 weeks by gavage, (III) 35 mg/kg lipoic acid once a week for 10 weeks by intraperitoneal injection, and (IV) CP plus lipoic acid (24 h prior to CP administration). Testicular toxicity, assessed by decreased enzymatic activities of lactate dehydrogenase and glucose-6-phosphate dehydrogenase, was reversed with lipoic acid pretreatment. CP-exposed rats (group II) showed abnormal levels of enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and glutathione reductase) and antioxidants (reduced glutathione, ascorbate and alpha-tocopherol) along with high malondialdehyde levels. In contrast, rats pretreated with lipoic acid (group IV) showed normal lipid peroxidation and antioxidant defenses. These findings indicate a cytoprotective role of lipoic acid in this experimental model of testicular toxicity.

Animals↗
PubMed2003

Effect of alpha lipoic acid on intracerebroventricular streptozotocin model of cognitive impairment in rats.

In the present study, the effect of alpha lipoic acid, a potent free radical scavenger, was investigated against the intracerebroventricular streptozotocin model of cognitive impairment in rats, which is characterized by a progressive deterioration of memory, cerebral glucose and energy metabolism, and oxidative stress. Wistar rats were injected with intracerebroventricular streptozotocin bilaterally. The rats were treated chronically with alpha lipoic acid (50, 100 and 200 mg/kg) orally for 21 days starting from day 1 of streptozotocin injection in separate groups. The learning and memory behavior was evaluated and the rats were sacrificed for estimation of oxidative stress. The intracerebroventricular streptozotocin rats treated with alpha lipoic acid (200 mg/kg, p.o.) showed significantly less cognitive impairment as compared to the vehicle treated rats. There was also an insignificant increase in oxidative stress in the alpha lipoic acid treated groups. The study demonstrated the effectiveness of alpha lipoic acid in preventing cognitive impairment and oxidative stress induced by intracerebroventricular streptozotocin and its potential in dementia associated with age and age related neurodegenerative disorders where oxidative stress is involved such as Alzheimer's disease.

Animals↗