Effects of Lipoic Acid and Dihydrolipoic Acid on 4-Aminophenol-Mediated Erythrocytic Toxicity in vitro (original) (raw)
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Free Radical Biology and Medicine, 2000
Lipoic acid supplementation has been found to be beneficial in preventing neurovascular abnormalities in diabetic neuropathy. Insufficient (Na ϩ ϩ K ϩ )-ATPase activity has been suggested as a contributing factor in the development of diabetic neuropathy. This study was undertaken to test the hypothesis that lipoic acid reduces lipid peroxidation and glycosylation and can increase the (Na ϩ ϩ K ϩ )-and Ca ϩϩ -ATPase activities in high glucose-exposed red blood cells (RBC). Washed normal human RBC were treated with normal (6 mM) and high glucose concentrations (45 mM) with 0 -0.2 mM lipoic acid (mixture of S and R sterioisomers) in a shaking water bath at 37°C for 24 h. There was a significant stimulation of glucose consumption by RBC in the presence of lipoic acid both in normal and high glucose-treated RBC. Lipoic acid significantly lowered the level of glycated hemoglobin (GHb) and lipid peroxidation in RBC exposed to high glucose concentrations. High glucose treatment significantly lowered the activities of (Na ϩ ϩ K ϩ )-and Ca ϩϩ -ATPases of RBC membranes. Lipoic acid addition significantly blocked the reduction in activities of (Na ϩ ϩ K ϩ )-and Ca ϩϩ -ATPases in high glucose-treated RBC. There were no differences in lipid peroxidation, GHb and (Na ϩ ϩ K ϩ )-and Ca ϩϩ -ATPase activity levels in normal glucose-treated RBC with and without lipoic acid. Thus, lipoic acid can lower lipid peroxidation and protein glycosylation, and increase (Na ϩ ϩ K ϩ )-and Ca ϩϩ -ATPase activities in high-glucose exposed RBC, which provides a potential mechanism by which lipoic acid may delay or inhibit the development of neuropathy in diabetes.
Lipoic acid acutely induces hypoglycemia in fasting nondiabetic and diabetic rats
Metabolism, 1999
Lipoic acid (LA) is a unique antioxidant that increases peripheral glucose utilization in diabetic patients. This study was conducted to investigate whether the inhibition of glucose production could be an additional mechanism for the action of LA. intravenous (IV) LA injection (100 or 60 mg/kg body weight) to fasting nondiabetic or streptozotocin (STZ)-induced diabetic rats caused a rapid reduction in blood glucose with no effect on circulating insulin levels. In vivo conversion of fructose to glucose was not inhibited by LA, whereas the gluconeogenesis flux from alanine was completely prevented. Reduced liver pyruvate carboxylase (PC) activity in vivo is suggested by the finding that LA induced a decrease in liver coenzyme A (CoA) content (44% and 28% reduction in nondiabetic and diabetic rats, respectively, compared with vehicle-treated animals) and liver acetyl CoA content (80% and 67% reduction in nondiabetic and diabetic rats, respectively). A reduction in plasma free carnitine (42% and 22% in nondiabetic and diabetic rats, respectively) was observed in LA-treated animals, and acylcarnitine levels were increased twofold. This could be attributed to elevated levels of C16 and C18 acylcarnitine, without a detectable accumulation of lipoylcarnitine. Under such conditions, a significant increase in the plasma free fatty acid (FFA) concentration (204% in nondiabetic and 151% in diabetic animals) with no elevation in [~-hydroxybutyrate levels was noted. In conclusion, this study suggests that short-term administration of LA at high dosage to normal and diabetic rats causes an inhibition of giuconeogenesis secondary to an interference with hepatic fatty acid oxidation. This may render LA an antihyperglycemic agent for the treatment of diabetic subjects, who display glucose overproduction as a major metabolic abnormality.
Free Radical Biology and Medicine, 1999
In the present cross-sectional study, the influence of ␣-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/(␣-tocopherol/cholesterol), was examined in 107 patients with diabetes mellitus. Patients receiving ␣-lipoic acid (600 mg/day for Ͼ 3 months) had significant lower ROOHs and a lower ROOH/(␣-tocopherol/cholesterol) ratio than those without ␣-lipoic acid treatment [ROOH: 4.76 Ϯ 2.49 vs. 7.16 Ϯ 3.22 mol/l; p Ͻ .0001] and [ROOH/(␣-tocopherol/cholesterol): 1.37 Ϯ 0.72 vs. 2.16 Ϯ 1.17; p Ͻ 0.0001]. In addition, the influence of glycemic control and albuminuria on ROOHs and on the ratio of ROOH/(␣-tocopherol/cholesterol) was examined in the presence and absence of ␣-lipoic acid treatment. Patients were subdivided into three groups based on (1) their HbA 1 levels (Ͻ7.5, 7.5-9.5, and Ͼ9.5%) and (2) their urinary albumin concentrations (Ͻ20, 20 -200, and Ͼ200 mg/l). Neither poor glycemic control, nor the presence of micro-or macroalbuminuria prevented the antioxidant effect of ␣-lipoic acid. Using stepwise multiple regression analysis, ␣-lipoic acid was found to be the only factor significantly predicting low ROOHs and a low ratio of ROOH/(␣-tocopherol/ cholesterol). These data provide evidence that treatment with ␣-lipoic acid improves significantly the imbalance between increased oxidative stress and depleted antioxidant defence even in patients with poor glycemic control and albuminuria.
European Journal of Nutrition, 2011
The aim of this study was to investigate whether the daily administration of α-lipoic acid (LA) during 4 weeks prevents the redox disturbance in red blood cells (RBC) described in diabetes Methods Multiple low-dose streptozotocin (STZ) diabetes was induced in rats by the administration of 40 mg/kg STZ intraperitoneally (i.p.) for 5 consecutive days. LA was applied at a dose of 10 mg/kg i.p. for 4 weeks, starting from the last day of STZ administration. Results The LA-treated diabetic rats exhibited a general systemic improvement, revealed as the near restoration of body weight and of essential biochemical parameters. The latter was displayed as decreased hyperglycemia, lower triglyceride levels and lower serum activities of alanine aminotransferases and aspartate aminotransferases that point to a general improvement of diabetes-linked organ "lesions". The LA-treated diabetic rats also exhibited significant alleviation of oxidative stress, manifested as decreased lipid peroxidation and lower glycation levels of serum proteins and hemoglobin, while the RBC exhibited increased activities of antioxidant enzymes and elevated levels of reduced glutathione. In RBC, this was accompanied by decreased post-translational glycosylation by O-bound β-N-acetylglucosamine (O-GlcNAc) of the antioxidant enzymes superoxide dismutase and catalase and of heat shock proteins HSP70 and HSP90. Conclusion LA through its powerful antioxidant activity preserves the structural and functional integrity of RBC in diabetes. The RBC can then assume a more efficient role as the first line of systemic defense against diabetic complications arising from oxidative stress-induced damage of other tissues and organs.
Clinical and Experimental Pharmacology and Physiology, 2002
Recently, ␣-lipoic acid (ALA) has gained considerable interest as an anti-oxidant. Various studies have indicated the antioxidant effects of ALA and its reduced form dihydrolipoic acid. Therefore, it appears that these compounds have important therapeutic potential in conditions where oxidative stress is involved. The aim of the present study was to investigate the effect of ALA supplementation on lipid peroxidation and anti-oxidant enzyme activities in various tissues in diabetic rats.
Diabetes Research and Clinical Practice, 2001
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 a-lipoic acid reduce oxidative stress and urinary albumin excretion. In this prospective, open and non-randomized study, the effect of a-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 a-lipoic acid per day. Only patients with an urinary albumin concentration B200 mg/l were included into the study. After 18 months of follow up, the plasma thrombomodulin level increased from 35.9 9 9.5 to 39.7 9 9.9 ng/ml (P B 0.05) in the control group. In the a-lipoic acid treated group the plasma thrombomodulin level decreased from 37.5 9 16.2 to 30.9 9 14.5 ng/ml (P B 0.01). The UAC increased in patients without a-lipoic acid treatment from 21.2 9 29.5 to 36.9 9 60.6 ng/l (P B0.05), but was unchanged with a-lipoic acid. It is postulated that the significant decrease in plasma thrombomodulin and failure of UAC to increase observed in the a-lipoic acid treated group is due to antioxidative effects of a-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.
In the present study, the effects of alpha lipoic acid (ALA) supplementation on glycemic control, lipid profile, vitamin C, lipid peroxidation and antioxidant enzymes in streptozotocin (STZ)-induced diabetic rats have been evaluated. This study was carried out on 80 male rats. The rats were divided into four equal groups of 20 rats each. Group Ι :( Control group): Injected with citrate buffer only. Group Π: (Diabetic group): Injected with a single intraperetinoel (i.p) dose of 50 mg/kg of streptozotocin for diabetes induction. Group III :( diabetic alpha lipoic acid treated group) and Group IV: (control alpha lipoic acid treated group). ALA was injected intrperetinoel in a daily dose of 54 mg/kg bw. Blood samples for serum separation and liver and kidney tissues were collected from all animal groups two times at 4 and 6 weeks from the onset of treatment with α-lipoic acid which begin after five weeks of diabetes induction. All sera were processed directly for determination of glucose, total cholesterol, triacylglycerols, HDL–C, LDL-C, VLDL-C and vitamin C in addition to liver and kidney L- malondialdehyde (L- MDA) and antioxidant enzymes were also determined. The obtained results revealed that, a significant increase in serum glucose, total cholesterol, triacylglycerols, LDLC, VLDL-C, HDL-C, vitamin C and L-MDA concentrations in liver and kidney as well as marked reduction in CAT, SOD and GpX activites of liver and kidney were observed in STZ-induced diabetic rats. Treatment with ALA to STZ-induced diabetic rats lowered serum glucose, total cholesterol, triacylglycerols, LDL-C, HDL-C concentration and lipid peroxidation of liver and kidney as well as significantly increased serum vitamin C and liver catalase activity. These results suggest that, ALA may be effective in controlling glycemic status and improving dyslipidemia and has the potential in reducing cardiovascular complications due to diabetes mellitus. In addition, treatment with ALA improved significantly the diabetes-induced deterioration of vitamin C and attenuates the status of antioxidant enzymes and biomarkers of oxidative stress produced by diabetes mellitus.
The present study aimed to assess some biochemical changes of oxidative stress in alloxan-induced diabetic rats with administration of lipoic acid. The experiment was carried out on 96 male rats. The group I (32 rats) was left as control (normal non-diabetic). Sixty-four rats were injected subcutaneously with alloxan (120 mg / kg.b.wt.) for induction of diabetes. Then it was divided into two equal groups, group II (diabetic without administration of lipoic acid) and group III (diabetic with administration of lipoic acid). Blood samples were collected from 8 rats of each group for separation of clear serum at 1 st , 2 nd , 3 rd and the 4 th week after administration for determination of glucose. Fresh liver and brain tissue samples (0.2 g) were collected from sacrificed rats and homogenized in ten volumes of (ice-cold phosphate saline pH: 7), then kept at-20 ºC for assay of malondialdehyde, reduced glutathione and liver glycogen. The obtained data revealed that serum glucose level was significantly decreased in the 3rd group as compared with the diabetic one. Also there was a significant decrease of liver glycogen in the diabetic group as compared with the non-diabetic control group. Moreover, significant decrease of reduced glutathione in both liver and brain tissues in diabetic group as compared with control. Lipoic acid caused a significant elevation in liver reduced glutathione as compared with the diabetic group, but without effect on brain. There was a significant rise in malondialdehyde in liver and brain tissues of diabetic group as compared with control. On the other hand there was a significant decrease of malondialdehyde in liver and brain tissues of diabetic rats with lipoic acid as compared with diabetic rats throughout the experiment period. It could be concluded that significant increase of malondialdehyde together with the decrease of reduced glutathione in the diabetic group: indicated the oxidative stress of induced diabetes. Also the study revealed that lipoic acid exerted a powerful antioxidant effect and therefore the diabetics should be supplemented regularly with this vitamin.
Diabetes and Alpha Lipoic Acid
Frontiers in Pharmacology, 2011
Diabetes mellitus is a multi-faceted metabolic disorder where there is increased oxidative stress that contributes to the pathogenesis of this debilitating disease. This has prompted several investigations into the use of antioxidants as a complementary therapeutic approach. Alpha lipoic acid, a naturally occurring dithiol compound which plays an essential role in mitochondrial bioenergetic reactions, has gained considerable attention as an antioxidant for use in managing diabetic complications. Lipoic acid quenches reactive oxygen species, chelates metal ions, and reduces the oxidized forms of other antioxidants such as vitamin C, vitamin E, and glutathione. It also boosts antioxidant defense system through Nrf-2-mediated antioxidant gene expression and by modulation of peroxisome proliferator activated receptors-regulated genes. ALA inhibits nuclear factor kappa B and activates AMPK in skeletal muscles, which in turn have a plethora of metabolic consequences. These diverse actions suggest that lipoic acid acts by multiple mechanisms, many of which have only been uncovered recently. In this review we briefly summarize the known biochemical properties of lipoic acid and then discussed the oxidative mechanisms implicated in diabetic complications and the mechanisms by which lipoic acid may ameliorate these reactions. The findings of some of the clinical trials in which lipoic acid administration has been tested in diabetic patients during the last 10 years are summarized. It appears that the clearest benefit of lipoic acid supplementation is in patients with diabetic neuropathy.