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PubMed2006

alpha-lipoic acid corrects late-phase supernormal retinal oxygenation response in experimental diabetic retinopathy.

PURPOSE: To test the hypothesis that preventative alpha-lipoic acid (LPA) treatment corrects an abnormal retinal oxygenation response in experimental diabetic retinopathy. METHODS: Retinal oxygenation (DeltaPO2) was measured by MRI before (room air [ra]) and during a 4-minute carbogen inhalation challenge in five groups: control Sprague-Dawley (SD) and Lewis (LEW) rats, 3- to 4-month diabetic SD and LEW rats, and 4-month diabetic LEW rats preventatively treated with a chow LPA admix (400 mg/kg per chow). Comparisons were made between the initial 2 minutes of oxygenation change (measured using ra and first carbogen periods [t1 - ra]) and the next 2-minute change (assessed with first and second carbogen periods [t2-t1]) for superior and inferior hemiretinal DeltaPO2. RESULTS: In control SD rats, DeltaPO2(t1-ra) > DeltaPO2(t2-t1) (P <0.05) was found panretinally. In diabetic SD rats, the superior, but not the inferior, hemiretina had subnormal DeltaPO2(t1- ra) (P < 0.05) and supernormal DeltaPO2(t2-t1) (P < 0.05). In control LEW rats, DeltaPO2(t1-ra) and DeltaPO2(t2-t1) were not significantly different (P > 0.05). Also, control and diabetic LEW rat panretinal DeltaPO2(t1-ra) were lower (P < 0.05) than in the respective SD groups. In diabetic LEW rats, a supernormal (P < 0.05) panretinal DeltaPO2(t2-t1) was found that could be corrected with preventative LPA treatment. CONCLUSIONS: These data support the hypothesis and suggest that the influence of strain differences on the interpretation of retinovascular DeltaPO2 as a surrogate of drug treatment efficacy for diabetic retinopathy may be minimized by measuring a late-phase supernormal response. The LPA data raise the possibility that oxidative stress contributes to diabetes-induced supernormal DeltaPO2.

Animals↗
PubMed2003

Protection against amyloid beta peptide and iron/hydrogen peroxide toxicity by alpha lipoic acid.

Current evidence supports the role of oxidative stress in the pathogenesis of neuron degeneration in Alzheimer's disease (AD). alpha-Lipoic acid (LA), an essential cofactor in mitochondrial dehydrogenase reactions, functions as an antioxidant and reduces oxidative stress in aged animals. Here, we describe the effects of LA and its reduced form, dihydrolipoic acid (DHLA), in neuron cultures treated with amyloid beta-peptide (Abeta 25-35) and iron/hydrogen peroxide (Fe/H2O2). Pretreatment of dissociated primary hippocampal cultures with LA significantly protected against Abeta and Fe/H2O2 toxicity. In contrast, concomitant treatment of cultures with LA and Fe/H2O2 significantly potentiated the toxicity. Decreased cell survival in cultures treated concomitantly with LA and Fe/H2O2 correlated with increased free radical production measured by dichlorofluorescein fluorescence. Treatment of cortical neurons with DHLA significantly protected glucose-transport against Fe/H2O2 or beta-mediated decreases although treatment with LA did not provide protection. These data suggest that DHLA, the reduced form of LA, significantly protects against both Abeta and Fe/H2O2 mediated toxicity. The data also suggest that concomitant exposure to LA and Fe/H2O2 significantly potentiates the oxidative stress. Overall, these data suggest that the oxidation state of LA is critical to its function and that in the absence of studies of LA/DHLA equilibria in human brain the use of LA as an antioxidant in disorders where there is increased Fe such as AD is of questionable efficacy.

Alzheimer Disease↗
PubMed1991

Effect of alpha-lipoic acid on the peripheral conversion of thyroxine to triiodothyronine and on serum lipid-, protein- and glucose levels.

The influence of alpha-lipoic acid (LA, thioctic acid, CAS 62-46-4) on thyroid hormone metabolism and serum lipid-, protein- and glucose levels was investigated. In the first setup of experiments administration of LA together with thyroxine (T4) for 9 days suppressed the T4 induced increase of T3 generation by 56%. This suppression was similar to that affected by 6-propylthiouracil (54%). LA or T4 alone did not affect the cholesterol level, but together they led to a reduction. LA decreased the triglyceride level by 45%; the decrease induced by T4 or LA plus T4 was not significant. Total protein and albumin levels decreased by LA plus T4 treatment when compared to the LA control. The slight increase in glucose level by LA or T4 alone was not observed when they were administered together. In the second setup of experiments the administration of T4 for 22 days increased the serum T3 level 3-fold. When LA was combined with T4 and the treatment continued, the T3 production decreased by 22%. T4 reduced cholesterol level by 30%, and LA plus T4 further reduced it by 47%. The triglycerides were not affected. A moderate decrease in total protein was observed after treatment with T4 plus LA; T4 and LA plus T4 decreased the albumin level. The decrease in serum glucose by T4 recovers by LA treatment. These results demonstrate that LA interferes with the production of T3 from T4 when it is co-administered with T4. The elevated level of T3, after T4 administration, is reduced by treatment with LA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

[Contribution of potentiometry in the presence of lipoic acid to the study and evaluation of the in vitro antibacterial effects of betalactams].

We used potentiometry to assess the reduction of lipoic acid by a culture of Escherichia coli incubated with a beta-lactam. Two significant chronometric parameters were determined: one evaluates the antibiotic's killing effect, while the other reflects the stimulative effect exerted by the drug on cell reductive activity. For different beta-lactams, we did a quantitative study of the relationship between the concentrations of the antibiotic and each of the two potentiometric parameters. On the basis of our results we classified the different beta-lactams according to the degree of their killing and stimulative effects. Our study shows that potentiometry can provide original quantitative information on the in vitro antibacterial effect of beta-lactams.

Anti-Bacterial Agents↗
PubMed1996

Neuroprotective effects of alpha-lipoic acid and its enantiomers demonstrated in rodent models of focal cerebral ischemia.

The purpose of this study was to investigate whether alpha-lipoic acid (LA), the oxidized form of the radical scavenger dihydrolipoic acid (DLA), protected brain tissue against ischemic damage and whether there were differences in the neuroprotective potencies between its enantiomers. We used the models of focal cerebral ischemia in mice and rats. The infarct area on the mouse brain surface and the infarct volume of the rat brain were determined by means of an image analyzing system. The LA was capable of reducing the infarct area only when it was administered subcutaneously, but not when it was administered intraperitoneally or into the cisterna magna. Both the R- and the S-enantiomer of LA protected brain tissue against ischemic damage, but their protective activities seemed to be related to the time period of pretreatment. In mice, both enantiomers revealed a similar neuroprotective potency when they were administered subcutaneously 1 or 2 hr before occlusion of the middle cerebral artery (MCA), whereas a longer time period of pretreatment (4 or 6 hr) failed to exert neuroprotection. In rats, subcutaneous pretreatment with R- or S-LA for 2 hr before ischemia significantly diminished the infarct volume. We assume that LA has to be reduced to DLA which finally causes neuroprotection.

Animals↗
PubMedDate not supplied

Heat shock protein 60 response to exercise in diabetes: effects of alpha-lipoic acid supplementation.

The pathophysiology of diabetes includes oxidative stress and impaired heat shock protein (HSP) expression. We studied the effects of alpha-lipoic acid (LA) supplementation for 8 weeks and acute exercise on HSP60 expression and the oxidative stress marker 4-hydroxynonenal adducts (4-HNE) in streptozotocin-induced diabetic (SID) and nondiabetic control rats. Diabetes was associated with decreased HSP60 in the heart and increased levels of HSP60 and 4-HNE in the liver. LA increased HSP60 in the liver of control and diabetic rats and decreased 4-HNE in the liver and heart. Acute exercise increased liver 4-HNE, which was offset by LA. In conclusion, diabetes induced oxidative stress and impaired myocardial HSP60 expression, while LA partially offsets these alterations in a tissue-specific manner.

Aldehydes↗
PubMed2002

Alpha-lipoic acid attenuates hyperglycemia and prevents glomerular mesangial matrix expansion in diabetes.

Previous studies demonstrated that 2 mo of dietary supplementation with alpha-lipoic acid (LA) prevented early glomerular injury in non-insulin-treated streptozotocin diabetic rats (D). The present study examined the effects of chronic LA supplementation (30 mg/kg body wt per d) on nephropathy in D after 7 mo of diabetes. Compared with control rats, D developed increased urinary excretion of albumin and transforming growth factor beta, renal insufficiency, glomerular mesangial matrix expansion, and glomerulosclerosis in association with depletion of glutathione and accumulation of malondialdehyde in renal cortex. LA prevented or ameliorated all of these changes in D. Because chronic LA supplementation also attenuated hyperglycemia in D after 3 mo, its effects on renal injury were compared with treatment of rats with sufficient insulin to maintain a level of glycemic control for the entire 7-mo period (D-INS) equivalent to that observed with LA during the final 4 mo. Despite superior longitudinal glycemic control in D-INS, urinary excretion of albumin and transforming growth factor beta, glomerular mesangial matrix expansion, the extent of glomerulosclerosis, and renal cortical malondialdehyde content were all significantly greater, whereas cortical glutathione content was lower than corresponding values in D given LA. Thus, the renoprotective effects of LA in D were not attributable to improved glycemic control alone but also likely reflected its antioxidant activity. The combined antioxidant and hypoglycemic actions of LA both may contribute to its utility in preventing renal injury and other complications of diabetes.

Albuminuria↗
PubMed2006

Synthesis, characterization and biological activity of chemically modified insulin derivative with alpha lipoic acid.

A novel chemically-modified insulin, epsilon-N(B29)-lipoyl insulin, was selectively prepared by the covalent linkage of alpha-lipoic acid (LA) to the epsilon-amino group of Lys(B29) of insulin without any protecting agent and analyzed by PAGE, HPLC, MALDI-TOF-MS. Monolipoyl- insulin maintained the glucose-lowering effect as well as native insulin and showed a longer duration of action than native insulin and an inhibitory effect towards trypsin degradation.

Animals↗
PubMed2006

Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial.

OBJECTIVE: The aim of this trial was to evaluate the effects of alpha-lipoic acid (ALA) on positive sensory symptoms and neuropathic deficits in diabetic patients with distal symmetric polyneuropathy (DSP). RESEARCH DESIGN AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 181 diabetic patients in Russia and Israel received once-daily oral doses of 600 mg (n = 45) (ALA600), 1,200 mg (n = 47) (ALA1200), and 1,800 mg (ALA1800) of ALA (n = 46) or placebo (n = 43) for 5 weeks after a 1-week placebo run-in period. The primary outcome measure was the change from baseline of the Total Symptom Score (TSS), including stabbing pain, burning pain, paresthesia, and asleep numbness of the feet. Secondary end points included individual symptoms of TSS, Neuropathy Symptoms and Change (NSC) score, Neuropathy Impairment Score (NIS), and patients' global assessment of efficacy. RESULTS: Mean TSS did not differ significantly at baseline among the treatment groups and on average decreased by 4.9 points (51%) in ALA600, 4.5 (48%) in ALA1200, and 4.7 (52%) in ALA1800 compared with 2.9 points (32%) in the placebo group (all P < 0.05 vs. placebo). The corresponding response rates (>/=50% reduction in TSS) were 62, 50, 56, and 26%, respectively. Significant improvements favoring all three ALA groups were also noted for stabbing and burning pain, the NSC score, and the patients' global assessment of efficacy. The NIS was numerically reduced. Safety analysis showed a dose-dependent increase in nausea, vomiting, and vertigo. CONCLUSIONS: Oral treatment with ALA for 5 weeks improved neuropathic symptoms and deficits in patients with DSP. An oral dose of 600 mg once daily appears to provide the optimum risk-to-benefit ratio.

Administration, Oral↗
PubMed2002

Effects of alpha lipoic acid, ascorbic acid-6-palmitate, and fish oil on the glutathione, malonaldehyde, and fatty acids levels in erythrocytes of streptozotocin induced diabetic male rats.

In this research, it has been aimed to evaluate the improvement effects of alpha lipoic acid (ALA), ascorbic acid-6-palmitate (AA6P), fish oil (FO), and their combination (COM) on some biochemical properties in erythrocytes of streptozotocin (STZ)-induced diabetic male rats. According to experimental results, glutathione (GSH) level in erythrocytes decreased in diabetes (P < 0.01), D + ALA, and D + AA6P groups (P < 0.001). Malonaldehyde (MA) level increased in diabetes (P < 0.05), D + FO, and D + COM groups (P < 0.001), but its level in D + AA6P and D + ALA groups was lower in diabetes group (P < 0.01). Total lipid level in diabetes and diabetes plus antioxidant administered groups were higher than control. Total cholesterol level was high in diabetes and D + ALA groups (P < 0.05), but its level reduced in D + FO compared to control and diabetes groups, P < 0.05, < 0.001, respectively. Total triglyceride (TTG) level was high in the D + ALA (P < 0.05) and D + COM (P < 0.001) groups. In contrast, TTG level in blood of diabetes group was higher than diabetes plus antioxidant and FO administered groups (P < 0.001). According to gas chromatography analysis results, while the palmitic acid raised in diabetes group (P < 0.05), stearic acid in D + FO, D + ALA, and diabetes groups was lower than control (P < 0.05), oleic acid reduced in D + COM and D + FO groups, but its level raised in D + AA6P and D + ALA groups (P < 0.01). As the linoleic acid (LA) elevated in ALA + D, D + AA6P, and diabetes groups, linolenic acid level in diabetes, D + AA6P, and D + FO groups was lower than control (P < 0.001). Arachidonic acid (AA) decreased in D + ALA, D+ AA6P, and diabetes groups (P < 0.01), but its level in D + COM and D + FO was higher than control (P < 0.05). Docosahexaenoic acid (DHA) increased in D + AA6P and D + COM (P < 0.05). While the total saturated fatty acid level raised in diabetes group, its level reduced in D + ALA and D + FO groups (P < 0.05). In contrast, total unsaturated fatty acid level in D + ALA and D + FO groups was higher than control (P < 0.05). In conclusion, present data have confirmed that the combination of the ALA, AA6P, and FO have improvement effects on the recycling of GSSG to reduced GSH in erythrocytes of diabetic rats, and in addition to this, oxidative stress was suppressed by ALA and AA6P, and unsaturated fatty acid degree was raised by the effects of ALA and FO.

Animals↗
PubMed2006

Alpha-lipoic acid suppresses the development of collagen-induced arthritis and protects against bone destruction in mice.

OBJECTIVE: To test the ability of alpha-lipoic acid (LA) to attenuate the development of collagen-induced arthritis (CIA) in mice. METHODS: Mice were divided into three groups and treated with intraperitoneal administration of LA (10 or 100 mg/kg) or placebo. Clinical, histologic, and biochemical parameters were assessed. Human synovial fibroblasts and peripheral blood mononuclear cells were cocultured in various concentrations of LA to evaluate the effects on osteoclastogenesis. RESULTS: LA was associated with a dose-dependent reduction of CIA, as well as preventing bone erosion and destructive changes. Intracellular reactive oxygen species in lymphocytes obtained from inguinal lymph nodes, which was significantly higher in CIA than control mice, was significantly reduced in CIA by LA. The concentrations of TNF-alpha, IL-1beta, and IL-6 in the paws, and synovial NF-kappaB binding, all of which were markedly higher in CIA than control mice, were reduced by treatment with LA. In addition, LA inhibited the formation of human osteoclasts in vitro. CONCLUSION: Amelioration of joint disease by LA was associated with reduction in oxidative stress, as well as inhibition of inflammatory cytokine activation and NF-kappaB DNA binding activity. Moreover, LA inhibited bone destruction in vivo and osteoclastogenesis in vitro. Collectively, these results indicate that LA may be a new adjunctive therapy for rheumatoid arthritis.

Animals↗
PubMed2006

[Estimation of the effect of lipoic acid in the rat's lung during lipopolysaccharide-induced oxidative stress].

UNLABELLED: The aim of this study was to investigate the effect of lipoic acid (LA) on lipid peroxidation, hydrogen peroxide concentration (H2O2), sulphydryl group (-SH) contents and total capacity protein a few hours after administration lipopolysaccharide (LPS) -induced oxidative stress in rats. MATERIALS AND METODS: Male albino Wistar rats were used in this study. The animals were divided into four groups, each group consisting of ten male animals. Control group received physiological saline alone i.v. The second group was given LA (60 mg/kg b.w., i.v.). The third second group received LPS (30 mg/kg b.w., i.v.). The fourth group received LPS (30 mg/kg b.w., i.v.) and after 0.5h received LA (60 mg/kg b.w., i.v.). In the lung homogenates were measured thiobarbituric acid reactants (TBARS), hydrogen peroxide concentration, -SH groups and protein contents. RESULTS: The administration of LA after to LPS -induced oxidative stress caused a significant decrease in TBARS and H2O2 concentrations (appropriate 3.65 +/- 0.2 microM and 0.014 +/- 0.008 microM) compared with the group treated with LPS (appropriate 6.030 +/- 0.16 microM and 0.189 +/- 0.03 microM). Treatment of LPS-injected rats with LA caused increase in -SH groups and protein concentration (p < 0.05). CONCLUSION: The early administration of LA a significant decreased symptoms of oxidative stress - induced LPS, that shows decrease in lipid peroxidation process, H2O2 concentration and increase in -SH groups and protein contents in rat's lung homogenates.

Animals↗
PubMedDate not supplied

Effect of alpha-lipoic acid supplementation on markers of protein oxidation in post-mitotic tissues of ageing rat.

In the present study, we investigated whether DL-alpha-lipoic acid (LA) supplementation could have prooxidant or antioxidant effects on oxidative protein damage parameters such as protein carbonyl (PCO), nitrotyrosine (NT), advanced oxidation protein products (AOPP), and protein thiol (P-SH), as well as oxidative stress parameters such as total thiol (T-SH), non-protein thiol (Np-SH), and lipid hydroperoxide (LHP) in the brain and the skeletal muscle tissue of aged rats. PCO, and NT levels were increased, AOPP and P-SH levels were not changed in the brain tissue of aged rats given LA supplementation. On the other hand, TSH, Np-SH, and LHP levels were decreased in the brain tissue of aged rats given LA supplementation. The levels of the same parameters were not significantly different in the skeletal muscle tissue of aged rats given LA supplementation. The increased levels of protein oxidation markers such as PCO, and NT in the brain tissue of LA-supplemented aged rats compared with non-supplemented aged rats may suggest that oxidative protein damage is increased in LA-supplemented aged rats. We assume that an explanation for our findings regarding LA supplementation on protein oxidation markers in the brain tissue of aged rats may be due to the prooxidant effects of LA. Depending on post-mitotic tissue type and dosage of LA, the prooxidant effects of LA supplementation, should be considered in future studies.

Aging↗
PubMed1995

Effect of alpha-lipoic acid and dihydrolipoic acid on ischemia/reperfusion injury of the heart and heart mitochondria.

The aim of the present study was to evaluate a possible interference of alpha-lipoic acid (LA) or its reduced form (dithiol dihydrolipoic acid = DHLA) in the cardiac ischemia/reperfusion injury both at the level of the intact organ and at the subcellular level of mitochondria. In order to follow the effect of LA on the ischemia/reperfusion injury of the heart the isolated perfused organ was subjected to total global ischemia and reperfusion in the presence and absence of different concentrations of LA. Treatment with 0.5 microM LA improved the recovery of hemodynamic parameters; electrophysiological parameters were not influenced. However, application of 10 microM LA to rat hearts further impaired the recovery of hemodynamic functions and prolonged the duration of severe rhythm disturbances in comparison to reperfusion of control hearts. Treatment of isolated mitochondria with any concentration of DHLA could not prevent the impairment of respiratory-linked energy conservation caused by the exposure of mitochondria to 'reperfusion' conditions. However, DHLA was effective in decreasing the formation and the existence of mitochondrial superoxide radicals (O2.-). Apart from its direct O(2.-)-scavenging activities DHLA was also found to control mitochondrial O2.- formation indirectly by regulating redox-cycling ubiquinone. It is suggested that impairment of this mitochondrial O2.- generator mitigates postischemic oxidative stress which in turn reduces damage to hemodynamic heart function.

Animals↗
PubMed2006

Lipoic acid inhibits expression of ICAM-1 and VCAM-1 by CNS endothelial cells and T cell migration into the spinal cord in experimental autoimmune encephalomyelitis.

Lipoic acid (LA) suppresses and treats murine experimental autoimmune encephalomyelitis (EAE), which models multiple sclerosis. However, the mechanisms by which LA mediates its effects in EAE are only partially known. In the present study, LA (25, 50 and 100 microg/ml) inhibited upregulation of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in tumor necrosis factor-alpha (TNF-alpha) stimulated cultured brain endothelial cells. Immunohistochemical analysis of spinal cords from SJL mice that had received LA (100 mg/kg/day) following immunization to induce EAE exhibited markedly reduced expression of ICAM-1 and VCAM-1 compared with that of EAE mice receiving saline. Co-localization analysis showed that ICAM-1 and VCAM-1 expression increased over endothelial cells (staining positive for von Willebrand factor, vWF) in EAE and that LA decreased the expression levels to that observed in naïve mice. Spinal cords from mice receiving LA had significantly reduced inflammation (decreased CD4 and CD11b staining) as compared to EAE mice that received saline. Overall, our data suggest that the anti-inflammatory effects of LA in EAE may be partly due to inhibition of ICAM-1 and VCAM-1 expression by central nervous system (CNS) endothelial cells.

Animals↗
PubMed2000

Determination of lipoic acid and dihydrolipoic acid in human plasma and urine by high-performance liquid chromatography with fluorimetric detection.

A highly sensitive method for the determination of alpha-lipoic acid (LA) and dihydrolipoic acid (DHLA) in human plasma and urine has been developed. Samples were acidified and extracted with organic solvent, and the free sulfhydryls of DHLA protected as the dicarboxyethylate by treatment with ethylchloroformate. The free carboxylic function of LA and the SH-protected DHLA were converted into their amide derivatives with the strong fluorophore 2-(4-aminophenyl)-6-methylbenzothiazole in the presence of a coupling agent and a base catalyst. The resulting fluorescent amides of both LA and DHLA were separated on a reversed-phase column (Ultrasphere C8) using simple isocratic elution with acetonitrile-water (80:20) and detected fluorimetrically (excitation 343, emission 423 nm). The method is highly sensitive, reproducible, and is easily applied for the simultaneous determination of LA and DHLA in biological samples.

Chromatography, High Pressure Liquid↗
PubMed1999

Alpha-lipoic acid supplementation: tissue glutathione homeostasis at rest and after exercise.

Antioxidant nutrients have demonstrated potential in protecting against exercise-induced oxidative stress. alpha-Lipoic acid (LA) is a proglutathione dietary supplement that is known to strengthen the antioxidant network. We studied the effect of intragastric LA supplementation (150 mg/kg, 8 wk) on tissue LA levels, glutathione metabolism, and lipid peroxidation in rats at rest and after exhaustive treadmill exercise. LA supplementation increased the level of free LA in the red gastrocnemius muscle and increased total glutathione levels in the liver and blood. The exercise-induced decrease in heart glutathione S-transferase activity was prevented by LA supplementation. Exhaustive exercise significantly increased thiobarbituric acid-reactive substance levels in the liver and red gastrocnemius muscle. LA supplementation protected against oxidative lipid damage in the heart, liver, and red gastrocnemius muscle. This study reports that orally supplemented LA is able to favorably influence tissue antioxidant defenses and counteract lipid peroxidation at rest and in response to exercise.

Analysis of Variance↗