R-Alpha Lipoic Acid
References:Lipoic acid improves glucose utilisation and prevents protein glycation and AGE formation. V. Thirunavukkarasu, A.T. Anitha Nandhini, C. V. Anuradha. Pharmazie. October 2005, Vol. 60, Issue: 10, Page(s): 772-775
Abstract: The present study investigates the antiglycating effect of α-lipoic acid (LA) in high fructose-fed rats in vivo and its potential to inhibit the process of glycation in vitro. In addition, the effect of LA on glucose utilisation in rat diaphragm was also studied. Rats fed a high fructose diet (60% total calories) were administered with 35 mg/kg b.w, lipoic acid (LA) intraperitoneally for 20 days. The effects of LA on plasma glucose, fructosamine, protein glycation and glycated haemoglobin in high fructose rats and on in vitro glycation were studied. In vitro utilization of glucose was carried out in normal rat diaphragm in the presence and absence of insulin in which LA was used as an additive. The contents of glucose, glycated protein, glycated haemoglobin and fructosamine were significantly lowered on LA administration to high fructose-fed rats. LA prevented in vitro glycation and the accumulation of advanced glycation end products. Further LA enhanced glucose utilization in the rat diaphragm. This effect was additive to that of insulin and did not interfere with the action of insulin. The findings provide evidence for the therapeutic utility of lipoic acid in diabetes and its complications.
Lipoic acid attenuates hypertension and improves insulin sensitivity, kallikrein activity and nitrite levels in high fructose-fed rats. Thirunavukkarasu,-V; Anitha-Nandhini,-A-T; Anuradha,-C-V. J-Comp-Physiol-[B]. 2004 Nov; 174(8): 587-92
Abstract: Chronic feeding of fructose to normal rats causes impaired glucose tolerance, loss of tissue sensitivity to insulin, hyperinsulinemia and hypertension. alpha-Lipoic acid (LA), a co-enzyme known for its potent antioxidant effects, stimulates insulin-mediated glucose uptake in clinical and experimental diabetes. The purpose of this study was to examine whether LA can mitigate fructose-induced insulin resistance and associated abnormalities. Male Wistar rats of body weights 150-170 g were divided into 4 groups containing 12 rats each. Control rats received a control diet containing starch and water ad libitum. Fructose rats received a fructose-enriched diet (>60% of total calories). Fructose + LA rats received a fructose diet and LA (35 mg/kg b.w.) intraperitoneally. Control + LA rats received a normal diet and LA (35 mg/kg b.w.) intraperitoneally. After the treatment period of 20 days, blood pressure (BP) was measured. Oral glucose-tolerance test, insulin-sensitivity index, urea and creatinine clearance tests, and plasma and urinary sodium and potassium levels were analysed. Kallikrein activity and nitrite content were assayed. Additionally, the activities of RBC-membrane Na(+)/K(+) ATPase and Ca(2+) ATPase enzymes were assayed. Fructose rats showed increased BP, decreased glucose tolerance, decreased insulin sensitivity and altered sodium and potassium levels and renal clearance. LA supplementation mitigated these alterations. The increase in BP was attenuated and the levels of biochemical parameters were brought close to normal. The BP-lowering effect of LA in fructose rats may be related to improvement in insulin sensitivity
The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. Farr, S A : Poon, H F : Dogrukol Ak, D : Drake, J : Banks, W A : Eyerman, E : Butterfield, D A : Morley, J E. J-Neurochem. 2003 Mar; 84(5): 1173-83
Abstract: Oxidative stress may play a crucial role in age-related neurodegenerative disorders. Here, we examined the ability of two antioxidants, alpha-lipoic acid (LA) and N-acetylcysteine (NAC), to reverse the cognitive deficits found in the SAMP8 mouse. By 12 months of age, this strain develops elevated levels of Abeta and severe deficits in learning and memory. We found that 12-month-old SAMP8 mice, in comparison with 4-month-old mice, had increased levels of protein carbonyls (an index of protein oxidation), increased TBARS (an index of lipid peroxidation) and a decrease in the weakly immobilized/strongly immobilized (W/S) ratio of the protein-specific spin label MAL-6 (an index of oxidation-induced conformational changes in synaptosomal membrane proteins). Chronic administration of either LA or NAC improved cognition of 12-month-old SAMP8 mice in both the T-maze footshock avoidance paradigm and the lever press appetitive task without inducing non-specific effects on motor activity, motivation to avoid shock, or body weight. These effects probably occurred directly within the brain, as NAC crossed the blood-brain barrier and accumulated in the brain. Furthermore, treatment of 12-month-old SAMP8 mice with LA reversed all three indexes of oxidative stress. These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants.
Lipoic acid prevents hypertension, hyperglycemia, and the increase in heart mitochondrial superoxide production . Midaoui,AE; Elimadi,A; Wu,L; Haddad,PS; de-Champlain, J. Am-J-Hypertens. 2003 Mar; 16(3): 173-9
Abstract: BACKGROUND: The present study was designed to investigate whether the effects of dietary supplementation with alpha-lipoic acid could prevent the increase in mitochondrial superoxide production in the heart as well as the enhanced formation of advanced glycation end-products (AGE) that are associated with the development of hypertension and insulin resistance in chronically glucose-fed rats. METHODS: Sprague Dawley rats were either given or not given a 10% D-glucose solution to drink during 4 weeks, combined either with a normal chow diet or with alpha-lipoic acid supplemented diet. The oxidative stress was evaluated by measuring the heart mitochondrial superoxide production using the lucigenin chemiluminescence method. The formation of AGE was also assessed in plasma and aorta. RESULTS: Chronic administration of glucose resulted in a 29% increase in blood pressure, 30% increase in glycemia, 286% increase in insulinemia, and 408% increase in insulin resistance index. Chronic glucose feeding also resulted in a 22% greater mitochondrial superoxide anion production in heart and in an increase of 63% in AGE content in aorta. Increases in blood pressure, aorta AGE content and heart mitochondrial superoxide production were prevented in the rats fed glucose supplemented with lipoic acid. The simultaneous treatment with lipoic acid also attenuated the rise in insulin levels as well as in insulin resistance in the glucose fed rats. CONCLUSIONS: These findings demonstrate that alpha-lipoic acid supplementation prevents development of hypertension and hyperglycemia, presumably through its antioxidative properties, as reflected by prevention of an increase in heart mitochondrial superoxide anion production and in AGE formation in the aorta of chronically glucose treated rats.
Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-L- carnitine and/or R-alpha -lipoic acid. Liu, Jiankang : Killilea, David W : Ames, Bruce N. Proc-Natl-Acad-Sci-U-S-A. 2002 Feb 19; 99(4): 1876-81
Abstract: We test whether the dysfunction with age of carnitine acetyltransferase (CAT), a key mitochondrial enzyme for fuel utilization, is due to decreased binding affinity for substrate and whether this substrate, fed to old rats, restores CAT activity. The kinetics of CAT were analyzed by using the brains of young and old rats and of old rats supplemented for 7 weeks with the CAT substrate acetyl-l-carnitine (ALCAR) and/or the mitochondrial antioxidant precursor R-alpha-lipoic acid (LA). Old rats, compared with young rats, showed a decrease in CAT activity and in CAT-binding affinity for both substrates, ALCAR and CoA. Feeding ALCAR or ALCAR plus LA to old rats significantly restored CAT-binding affinity for ALCAR and CoA, and CAT activity. To explore the underlying mechanism, lipid peroxidation and total iron and copper levels were assayed; all increased in old rats. Feeding old rats LA or LA plus ALCAR inhibited lipid peroxidation but did not decrease iron and copper levels. Ex vivo oxidation of young-rat brain with Fe(II) caused loss of CAT activity and binding affinity. In vitro oxidation of purified CAT with Fe(II) inactivated the enzyme but did not alter binding affinity. However, in vitro treatment of CAT with the lipid peroxidation products malondialdehyde or 4-hydroxy-nonenal caused a decrease in CAT-binding affinity and activity, thus mimicking age-related change. Preincubation of CAT with ALCAR or CoA prevented malondialdehyde-induced dysfunction. Thus, feeding old rats high levels of key mitochondrial metabolites can ameliorate oxidative damage, enzyme activity, substrate-binding affinity, and mitochondrial dysfunction
Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid. Liu, Jiankang : Head, Elizabeth : Gharib, Afshin M : Yuan, Wenjun : Ingersoll, Russell T : Hagen, Tory M : Cotman, Carl W : Ames, Bruce N. Proc-Natl-Acad-Sci-U-S-A. 2002 Feb 19; 99(4): 2356-61
Abstract: Accumulation of oxidative damage to mitochondria, protein, and nucleic acid in the brain may lead to neuronal and cognitive dysfunction. The effects on cognitive function, brain mitochondrial structure, and biomarkers of oxidative damage were studied after feeding old rats two mitochondrial metabolites, acetyl-l-carnitine (ALCAR) [0.5% or 0.2% (wt/vol) in drinking water], and/or R-alpha-lipoic acid (LA) [0.2% or 0.1% (wt/wt) in diet]. Spatial memory was assessed by using the Morris water maze; temporal memory was tested by using the peak procedure (a time-discrimination procedure). Dietary supplementation with ALCAR and/or LA improved memory, the combination being the most effective for two different tests of spatial memory (P less than 0.05; P less than 0.01) and for temporal memory (P less than 0.05). Immunohistochemical analysis showed that oxidative damage to nucleic acids (8-hydroxyguanosine and 8-hydroxy-2'-deoxyguanosine) increased with age in the hippocampus, a region important for memory. Oxidative damage to nucleic acids occurred predominantly in RNA. Dietary administration of ALCAR and/or LA significantly reduced the extent of oxidized RNA, the combination being the most effective. Electron microscopic studies in the hippocampus showed that ALCAR and/or LA reversed age-associated mitochondrial structural decay. These results suggest that feeding ALCAR and LA to old rats improves performance on memory tasks by lowering oxidative damage and improving mitochondrial function.
Effect of DL-alpha-lipoic acid on the status of lipid peroxidation and antioxidant enzymes in various brain regions of aged rats. Arivazhagan, P : Shila, S : Kumaran, S : Panneerselvam, C. Exp-Gerontol. 2002 Jun; 37(6): 803-11
Abstract: The effect of DL-alpha-lipoic acid on lipid peroxidation and antioxidant enzymes were evaluated in various brain regions of young and aged rats. Lipoate contents of discrete brain regions were also measured. In aged rats, the activities of superoxide dismutase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase were low whereas thiobarbituric acid reactive substances were found to be high. Catalase activity in various brain regions was little altered in aged rats. Lipoic acid an antioxidant was administered intraperitoneally (100mg/kg body weight per day) for 7 and 14 days. Lipoate administered aged rats showed a duration dependent reduction in the level of lipid peroxidation and elevation in the activities of antioxidant enzymes. There was a rise in the level of lipoate in aged rats after supplementation of lipoate in all the brain regions examined. From our results we conclude that lipoate supplementation had a beneficial effect in both preventing and reversing abnormalities in ageing brain. This beneficial effect was associated with normalization of lipid peroxidation and partial restoration in the activities of various enzymatic antioxidants suggesting that lipoate supplementation could improve brain antioxidant functions in the elderly.
Alpha-lipoic acid prevents ethanol-induced protein oxidation in mouse hippocampal HT22 cells. Pirlich, M : Kiok, K : Sandig, G : Lochs, H : Grune, T. Neurosci-Lett. 2002 Aug 9; 328(2): 93-6
Abstract: Oxidative stress is involved in a number of neurological disorders, including the neurotoxic effects of ethanol. Recent studies have described a neuroprotective potential of alpha-lipoic acid (LC) in several models of neuronal cell death related to oxidative stress. We tested the hypothesis that LC could be effective in preventing ethanol-induced neurotoxicity employing the clonal hippocampa cell line HT22. A 24 h incubation with ethanol 100-600 mM caused a dose-dependent loss of cell viability and a significant increase of the overall intracellular protein oxidation. Coincubation with LC 0.1 mM resulted in a significant decrease of ethanol-related neurotoxicity and a complete prevention of the ethanol-induced intracellular protein oxidation. These results indicate that the radical scavenging properties of LC are effective to ameliorate ethanol-induced neurotoxicity.
The neuroprotective antioxidant alpha-lipoic acid induces detoxication enzymes in cultured astroglial cells. Flier, J : Van Muiswinkel, F L : Jongenelen, C A : Drukarch, B. Free-Radic-Res. 2002 Jun; 36(6): 695-9
Abstract: alpha-Lipoic acid (LA), an antioxidant with broad neuroprotective capacity, is thought to act by scavenging reactive oxygen species and stimulation of glutathione synthesis. LA shows structural resemblance to dithiolethiones, like anethole dithiolethione (ADT). ADT protects against oxidative damage, primarily by induction of phase II detoxication enzymes, in particular NAD(P)H:quinone oxidoreductase (NQO1) and glutathione-S-transferase (GST). Therefore, we investigated whether LA, like ADT, is capable also of inducing these protective enzymes. Our data show that LA, like ADT, induces a highly significant, time- and concentration dependent, increase in the activity of NQO1 and GST in C6 astroglial cells. The LA or ADT mediated induction of NQO1 was further confirmed by quantitative PCR and western blot analysis. This work for the first time unequivocally demonstrates LA mediated upregulation of phase II detoxication enzymes, which may highly contribute to the compounds' neuroprotective potential. Moreover, the data support the notion of a common mechanism of action of LA and ADT.
Effect of DL-alpha-lipoic acid on glutathione metabolic enzymes in aged rats. Arivazhagan, P : Ramanathan, K : Panneerselvam, C. Exp-Gerontol. 2001 Dec; 37(1): 81-7
Abstract: Ageing is characterized by a failure to maintain homeostasis under conditions of physiological stress, with an increasing susceptibility to disease and death. The accumulation of errors committed by faulty biochemical reactions over a vast period generates the cumulative effect observed during ageing. The most notable among the effects of ageing are the age-related disorders where free radicals are the major cause. When the level of free radicals increases because of diet, lifestyle, environment or other influences, it results in subsequent reduction of antioxidants. Reduced glutathione is one of the most fascinating molecules virtually present in all animal cells in often quite higher concentrations. An essential mechanism that accounts for most of the metabolic and cell regulatory properties of glutathione is the thiol disulfide exchange equilibria. We evaluated the age-associated alterations in glutathione dependent enzymes, glutathione and hydroxyl radicals in young and aged rats with respect to lipoate supplementation. In aged rats, activities of glutathione peroxidase, glutathione reductase, glutathione-S-transferase and glucose-6-phosphate dehydrogenase and the level of glutathione were low, whereas the level of hydroxyl radical was higher than in the young ones. Administration of DL-alpha-lipoic acid, a thiol antioxidant intraperitoneally to the aged rats, led to a time-dependent reduction in hydroxyl radicals and elevation in the activities/level of glutathione systems. Hence it can be suggested that lipoate, a dithiol prevents the oxidation of reduced glutathione and protects its related enzymes from peroxidative damage.
Alpha-lipoic acid protects rat cortical neurons against cell death induced by amyloid and hydrogen peroxide through the Akt signalling pathway. Zhang, L : Xing, G Q : Barker, J L : Chang, Y : Maric, D : Ma, W : Li, B S : Rubinow, D R. Neurosci-Lett. 2001 Oct 26; 312(3): 125-8
Abstract: Substantial evidence suggests that the accumulation of beta-amyloid (Abeta)-derived peptides contributes to the aetiology of Alzheimer's disease (AD) by stimulating formation of free radicals. Thus, the antioxidant alpha-lipoate, which is able to cross the blood-brain barrier, would seem an ideal substance in the treatment of AD. We have investigated the potential effectiveness of alpha-lipoic acid (LA) against cytotoxicity induced by Abeta peptide (31-35) (30 microM) and hydrogen peroxide (H(2)O(2)) (100 microM) with the cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reduction and fluorescence dye propidium iodide assays in primary neurons of rat cerebral cortex. We found that treatment with LA protected cortical neurons against cytotoxicity induced by Abeta or H(2)O(2). In addition, LA-induced increase in the level of Akt in the neurons was observed by Western blot. The LA-induced neuroprotection and Akt increase were attenuated by pre-treatment with the phosphatidylinositol 3-kinase inhibitor, LY294002 (50 microM). Our data suggest that the neuroprotective effects of the antioxidant LA are partly mediated through activation of the PKB/Akt signaling pathway
Effect of DL-alpha-lipoic acid on mitochondrial enzymes in aged rats. Arivazhagan, P : Ramanathan, K : Panneerselvam, C. Chem-Biol-Interact. 2001 Nov 28; 138(2): 189-98
Abstract: Mitochondrial dysfunction appears to contribute to some of the loss of function accompanying ageing. Mitochondria from aged tissue use oxygen inefficiently impairing ATP synthesis and results in increased oxidant production. A high flux of oxidants not only damages mitochondria, but other important cell biomolecules as well. In the present investigation, the levels of lipid peroxidation, oxidized glutathione, non-enzymatic antioxidants and the activities of mitochondrial enzymes were measured in liver and kidney mitochondria of young and aged rats before and after lipoic acid supplementation. In both liver and kidney increase in the levels of mitochondrial lipid peroxidation and oxidized glutathione and decrease in the levels of antioxidants and the activities of mitochondrial enzymes were observed in aged rats. DL-alpha-lipoic acid supplemented aged rats showed a decrease in the levels of lipid peroxidation and oxidized glutathione and increase in the levels of reduced glutathione, vitamins C and E and the activities of mitochondrial enzymes like isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, NADH-dehydrogenase and cytochrome-c-oxidase. Thus, lipoic acid reverses the age-associated decline in endogenous low molecular weight antioxidants and mitochondrial enzymes and, therefore, may lower the increased risk of oxidative damage that occurs during ageing. From our results it can be concluded that lipoic acid supplementation enhances the activities of mitochondrial enzymes and antioxidant status and thereby protects mitochondria from ageing.