Administration Of Alpha-lipoic Acid Research Articles

Treatment of experimental autoimmune encephalomyelitis with alpha lipoic acid and associative conditioning

We have initiated studies to evaluate the suitability of performing therapeutic conditioning trials in experimental autoimmune encephalomyelitis (EAE) mice treated with alpha lipoic acid (ALA). EAE was induced in SJL mice by active immunization with myelin antigen. Once daily subcutaneous injection of ALA served as the unconditional stimulus (US) administered with the conditional stimulus (CS) saccharin-flavored drinking water under a regimen of restricted water access. In the first study, we found that water restriction and saccharin administration were compatible with disease development and effective ALA treatment of EAE mice. In the second study, mice were conditioned to once daily administration of ALA paired with administration of saccharin-flavored water (US+CS) on days 7–16. Test trials spanned experimental days 17–32 in groups receiving either saccharin-flavored water (CS, in the experimental group) versus unflavored water (CSo, in the control group) and compared several measures of EAE severity using multivariate ANOVA (MANOVA). Reduced disease severity in the experimental group (US+CS:CS) compared to the control group (US+CS:CSo) suggested that conditioning had occurred. These results demonstrate an approach for conducting therapeutic conditioning trials in EAE mice and suggest considerations for future investigations.

Curative effect of alpha-lipoic acid on peripheral neuropathy in type 2 diabetes: a clinical study

To evaluate the effect of alpha-lipoic acid (ALA) on diabetic peripheral neuropathy (DPN). 95 type 2 diabetic patients complicated with DPN were randomly divided into 2 groups: treatment group (n = 52), receiving ALA 600 mg/d in normal saline 250 ml given by intravenous drip infusion once a day for 14 days; and control group (n = 43), administered with radix salviae 20 ml by intravenous drip infusion once a day for 14 days. Before and 7 and 14 days after the management fasting glucose (FPG), fasting insulin (FINS), supersensitive C reactive protein (sCRP), and HbA1c were measured, and total symptom score (TSS) and Michigan neuropathy screening instrument (MNSI) were used to evaluate the nervous symptoms. 50 cases of the treatment group and 43 control cases completed the study. Compared with the control group, the TSS of the treatment group reduced significantly after 1 week, but the MNSI score did not change significantly. The TSS 7d after ALA administration of the treatment group was significantly lower than that before the ALA treatment in the same group and that of the control group 7 days after the radix salviae infusion as well (both P < 0.05). The TSS and MNSI score 14 days after the management of the treatment group were significantly lower than those of the control group (both P < 0.01). The symptom scores of numbness, sting sensation, and burning sensation reduced significantly 2-weeks after ALA treatment, but there were no significant differences in these symptoms after the management in the control group. The total gratification rate of the treatment group was 90% (45/50), significantly higher than hat of the control group (13.95%, 6/43, P < 0.01). One patient of the 50 patients receiving ALA treatment felt chest distress 2 days after ALA administration, but the symptom was improved in the same day after the velocity of intravenous drip was slowed down, and no other adverse effects were found in these two groups. ALA effectively improves the sensitive symptoms of DPN patients and is safe for most of the patients.

α-Lipoic acid increases cardiac glucose oxidation independent of AMP-activated protein kinase in isolated working rat hearts

Alpha-lipoic acid (ALA) is a naturally occurring enantiomer of lipoic acid and is a cofactor of key metabolic enzyme complexes catalyzing the decarboxylation of alpha-keto acids. It was recently shown that ALA increases insulin sensitivity by activating AMP-activated protein kinase (AMPK) in skeletal muscle. Also, administration of ALA to obese rats increases insulin-stimulated glucose uptake in the whole body. We investigated the metabolic effects of ALA on isolated working rat hearts. ALA (500 microM) stimulated glucose oxidation (157+/-31 nmol.dry wt(-1).min(-1) in control vs 315+/-63 nmol.dry wt(-1).min(-1) in ALA-treated, p<0.05) without affecting glycolysis, lactate oxidation, or palmitate oxidation. Cardiac work was not affected by ALA treatment. The effect of ALA on glucose oxidation was not associated with an activation of AMPK. AMPK activity was 190+/-14 pmol.mg protein(-1).min(-1) in control vs 190+/-16 pmol.mg protein(-1).min(-1) in ALA-treated hearts. This study shows that ALA stimulates glucose oxidation in isolated working rat hearts independent of AMPK activation. The beneficial effects of ALA treatment in diabetic patients may be at least in part related to its effect on glucose metabolism.

The Effect of Alpha-Lipoic Acid on the Protection of Epidermal Nerve Fibers and Microcapillaries in the Streptozotocin-Induced Diabetic Rats

Background: Diabetic neuropathy is associat ed with risk factors for macrov ascular diseases and other microvascular complications. Alpha-lipoic acid (ALA) administra tion has been reported to improve metabolic abnormalities and ameliorate peripheral polyneuropathy in diabe tic patients. In addition, ALA improves endoneurial nutritive neural blood flow and nerve conduction velocity in diabetic rats. But it is not clear whether ALA has a preservation effect on microvasculature in addition to the effect on intraepidermal nerve fibers (IENFs). We investigated the effect of ALA on intraepide rmal nerve fiber density (numbers/mm) and cutaneous capillary length in streptozotocin-induced diabetic rats. Methods: The rats were randomly divided into 3 groups: diabetes without diet control, diabetes with diet control, and diabetes with ALA treatment. Diabetes was induced by a single intraperitoneal injection of streptozotocin (60 mg/kg) and the effect of ALA treatment was assessed by IENF immunostained with protein gene product 9.5 and by quantification of total cutaneous capillary length with mouse anti-rat reca-1 immunostaining. Results: The value of IENF density significantly increased in ALA treat ment group compared with other groups (P < 0.05). Quantification of microvascularity was also significantly increased in ALA treatment group compared with other groups (P < 0.05). Conclusion: The results of this study suggest that ALA administration in diabetic rats may be beneficial in the prevention of peripheral neuropathy associated with improvement of microvascularity. And the symptomatic amelioration after ALA treatment may be attributed to this morphological improvement. (J Kor Diabetes Assoc 31:488~497, 2007)

Improvement of insulin sensitivity in patients with type 2 diabetes mellitus after oral administration of alpha-lipoic acid

Amelioration of insulin resistance could improve both glycaemic control and cardiovascular risk factors in patients with type 2 diabetes mellitus. Alpha-lipoic acid has been shown to improve insulin action after parenteral administration. the aim of the study was to assess the effect of oral administration of alpha-lipoic acid on insulin sensitivity in patients with type 2 diabetes. twelve patients (mean+/-sD; age 52.9+/-9.9 yrs; body mass index 33.9+/-7.4 kg/m(2)) were treated with oral alpha-lipoic acid, 600 mg twice daily over a period of 4 weeks. twelve subjects with normal glucose tolerance served as a control group in terms of insulin sensitivity (Is). Is was measured by a 2h manual hyperinsulinaemic (insulin infusion rate-40 mU/m(2 )body surface area/min) euglycaemic (blood glucose kept at 5 mmol/l) clamp technique and expressed as a glucose disposal rate (M) and insulin sensitivity index (IsI). At the end of the treatment period, Is of diabetic patients was significantly increased: M from 3.202+/-1.898 to 5.951+/-2.705 mg/kg/min (mean+/-sD), p<0.01; and IsI from 4.706+/-2.666 to 7.673+/-3.559 mg/kg/min per mIU/l x 100 (mean+/-sD), p<0.05. the difference was not statistically significant between the Is of diabetic patients after alpha-lipoic acid therapy and control subjects. short-term oral alpha-lipoic acid treatment increases peripheral insulin sensitivity in patients with type 2 diabetes mellitus.

The Effect of Oral Administration of Alpha Lipoic Acid and Alpha Lipoic Acid Coated Stent in Porcine In-Stent Restenosis Model

Background and Objectives:Alpha lipoic acid (ALA) is beneficial for improving endothelial dysfunction and preventing atherosclerosis-related diseases. We evaluated the affect of ALA on stent restenosis in a porcine model. Materials and Methods:The First experiment: Balloon overdilation injuries were performed in two coronary arteries in 12 pigs. Four weeks after the balloon overdilation injury, 24 bare metal stents were placed for 24 injured coronary arteries. We randomized into two groups (12 stents per group; control group: aspirin and clopidogrel only, ALA group: aspirin and clopidogrel plus 100 mg/kg ALA during 4 weeks). The Second experiment: Stents were randomly implanted in 2 coronary arteries in 8 pigs. Group I was the control stent group (n=8), and group II was the ALA coated stent group (n=8). Follow-up coronary angiogram and histopathologic assessment were performed at 4 weeks after stenting in both experiments. Results:The First experiment On histopathologic analysis, the injury score and internal elastic lamina area did not differ significantly between the two groups. The neointimal area was 7.3±0.9 mm in the control group and 2.2±1.1 mm in the ALA group (p<0.001), and the histopathologic area of stenosis was 75.9±8.5% in the control group and 23.5±10.5% in the ALA group (p<0.001). The Second experiment: The injury score and internal elastic lamina area were not significantly different between the two groups. The neointimal area was 7.4±1.1 mm in the control group and 1.4±0.8 mm in the ALA group (p<0.001), and the histopathologic area of stenosis was 77.6±10.9% in the control group and 15.6±7.6% in the ALA group (p<0.001). Conclusion:Both a high dose of oral ALA and ALA coated stents inhibited neointimal hyperplasia in this porcine coronary artery stent restenosis model. (Korean Circulation J 2006;36:495-502)

Plasma protein oxidation in aging rats after alpha-lipoic acid administration

In the present study, we investigated whether alpha-lipoic acid administration could have prooxidant or antioxidant effect on oxidative protein damage parameters such as protein carbonyl, nitrotyrosine, advanced oxidation protein products, and protein thiol, as well as oxidative stress parameters such as total thiol, nonprotein thiol, and lipid hydroperoxide in the plasma proteins of aged rats. Alpha-lipoic acid (100 mg/kg body wt/day) was administrated intraperitoneally to the Sprague-Dawley rats for 14 days. Protein carbonyl, nitrotyrosine, and advanced oxidation protein products levels were increased, protein thiol, nonprotein thiol, and total thiol levels were not changed in the plasma proteins of aged rats with alpha-lipoic acid administration. In aging rats with and without alpha-lipoic acid administration, plasma lipid hydroperoxide levels were significantly increased compared with those of the control group. The increased levels of protein oxidation markers such as protein carbonyl, nitrotyrosine and advanced oxidation protein products in the plasma proteins of alpha-lipoic acid-administrated aged rats compared with nonadministrated aged rats suggests that protein oxidation is increased in alpha-lipoic acid-administrated aged rats. We assume that an explanation for our findings regarding alpha-lipoic acid administration on protein oxidation markers in the plasma proteins of aged rats may be due to the prooxidant effects of alpha-lipoic acid.

Protective effect of alpha-lipoic acid against chloroquine-induced hepatotoxicity in rats.

Oral administration of a-lipoic acid, a metavitamin, was investigated for its possible hepatoprotective effect in Wistar rats against chloroquine-induced toxicity. Rats were treated orally with alpha-lipoic acid (10, 30 and 100 mg x kg(-1) day(-1)) for 7 days before a single oral administration of chloroquine (970 mg x kg(-1) day(-1)) and alpha-lipoic acid treatment was continued for three more days. The increased level of serum enzymes (aspartate transaminase, alanine transaminase and alkaline phosphatase), bilirubin, lipids and plasma thiobarbituric acid-reactive substances (TBARS) and hydroperoxides observed in rats treated with chloroquine were very much reduced in rats treated with alpha-lipoic acid plus chloroquine. A significant decrease in plasma antioxidants such as reduced glutathione (GSH), vitamin C and vitamin E were observed in chloroquine-treated rats when compared with control rats. Administration of alpha-lipoic acid significantly improved the levels of plasma antioxidants GSH, vitamin C and vitamin E in chloroquine-treated rats. In the case of 100 mg x kg(-1) day(-1) the effect was highly significant compared with the other doses (10 and 30 mg x kg(-1) day(-1)). The results of the study revealed that alpha-lipoic acid could offer protection against chloroquine-induced hepatotoxicity. alpha-Lipoic acid had a better protective effect when compared with silymarin, a reference drug.

Glutathione and alpha-lipoate in diabetic rats: nerve function, blood flow and oxidative state.

Increased oxidative stress is considered to be a causal factor in the development of diabetic complications, among which peripheral neuropathy. The pathophysiology of nerve dysfunction in diabetes has been explained both by reduced endoneurial microcirculation and alterations in endoneurial metabolism. It is unclear whether antioxidants primarily improve nerve blood flow or normalise systemic or endoneurial oxidative metabolism. Therefore, we evaluated the effects of the antioxidants glutathione and alpha-lipoic acid on both nerve microcirculation and the antioxidative capacity and lipid peroxidation in experimentally diabetic rats. Streptozotocin-diabetic rats were treated with different doses of alpha-lipoic acid, reduced glutathione or placebo, and were compared with nondiabetic controls. We measured systemic and endoneurial antioxidants, malondialdehyde and whole blood hydrogen peroxide. Furthermore, we evaluated sciatic and tibial motor and sensory nerve conduction velocity, caudal nerve conduction velocity, and assessed sciatic nerve blood flow and vascular resistance by Laser-Doppler flowmetry. We observed a rise in erythrocyte glutathione by 27 % (P < 0.05), and a trend towards decreased plasma malondialdehyde in alpha-lipoic acid, but not in glutathione-treated animals in comparison with the placebo group. Simultaneously, sciatic nerve blood flow and vascular resistance were improved by daily alpha-lipoic acid administration by 38% (P < 0.05). Peripheral nerve conduction velocity and endoneurial glutathione were not significantly influenced by antioxidant treatment. Only minor beneficial effects of alpha-lipoic acid on nerve blood flow and oxidative state occur at the given doses; these effects were insufficient to improve nerve conduction deficits.

Antioxidant activities of dithiol alpha-lipoic acid

Alpha-lipoic acid, a dithiol compound derived from octanoic acid, which acts as a coenzyme for several redox reactions in almost all the tissue of the body. It retains its protective functions in both oxidized and reduced forms. Alpha-lipoic acid reduces oxidative stress by redox generation of other antioxidants such as vitamin C, E and increasing the intracellular glutathione. Exogenous alpha-lipoic acid has been shown to increase ATP production due to its role in the oxidation of pyruvate and alpha-ketoglutarate in the mitochondria. Alpha-lipoic acid administration has been shown to be effective in preventing pathology in various experimental models in which reactive oxygen species have been implicated. Key words: Antioxidant, free radical, alpha-lipoic acid DOI: 10.3329/bjms.v8i3.3982 Bangladesh Journal of Medical Sciences Vol.8(3) 2009 p46-51