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Abstracts

Abstracts

Antioxidant

Antioxidant

Alpha-Lipoic acid, which plays an essential role in mitochondrial dehydrogenase reactions, has recently gained considerable attention as an antioxidant. Review the properties of lipoate in terms of:

(1) reactions with reactive oxygen species;
(2) interactions with other antioxidants;
(3) beneficial effects in oxidative stress models or clinical conditions.

Lipoate, or its reduced form, dihydrolipoate, reacts with reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects membranes by interacting with vitamin C and glutathione, which m in turn recycle vitamin E.

Additionally, dihydrolipoate may exert prooxidant actions through reduction of iron.

Furthermore, lipoate can function as a redox regulator of proteins such as myoglobin, prolactin, thioredoxin and NF-kappa B transcription factor.

Packer, L. et al: Alpha-Lipoic Acid as a biological antioxidant. Free Radical Biology & Medicine, 1995, 19(2): 227 - 250.

HIV & Alpha Lipoic Acid

HIV

Gene expression of human immunodeficiency virus (HIV) depends on host cellular transcription factors including nuclear factor-kappab (NF-kappaB). The involvement of reactive oxygen intermediates (ROI) has been implicated as intracellular messengers in the inducible activation of NF-kappaB.

This study compared the efficacy of two antioxidants, alpha-lipoic acid (LA) and N-acetylcysteine (NAC), which are widely recognized NF-kappaB inhibitors.

LA demonstrated more potent activity.

0.2 mM LA could cause 40% reduction in the HIV- I expression from the TNF-alpha-stimulated OM IO. 1, a cell line latently infected with HIV- 1. On the other hand, IO mM NAC was required to elicit the same effect.

Merin JP et al: Alpha-lipoic acid blocks HIV-1 LTR-dependent expression of hygromycin resistance in THP-1 stable transformants. FEBS Lett 1996 Sep 23;394(1):9-13.

Peroxynitrite

Peroxynitrite

Peroxynitrite, formed by combining superoxide radical with nitric oxide, is a reactive tissue-damaging species apparently involved in the pathology of several human diseases. Peroxynitrite nitrates tyrosine residues and inactivates alpha I -antiproteinase.

Both lipoic and dihydrolipoic, acid efficiently protect against damage by peroxynitrite. By contrast, other disulphides tested did not. The biological antioxidant effects of lipoate/dihydrolipoate may involve scavenging of reactive nitrogen species as well as reactive oxygen species.

Whiteman, M. et al: Protection against peroxynitrite-dependent tyrosine nitration and alpha 1-antiproteinase inactivation by oxidized and reduced lipoic acid. FEBS Lett. 1996, 379(1): 74 - 76.

Antioxidant Supplement

Antioxidant Supplement

According to this study, orally supplemented lipoic acid may influence tissue antioxidant defenses and counteract lipid peroxidation at rest and in reaction to exercise. In the clinical trial, LA supplementation increased the level of free LA in the red gastrocnemius muscle and increased total glutathione levels in the liver and blood. LA may act as preventive agent against oxidative stress induced by exercise.

Khanna S, Atalay M, Laaksonen DE, Gul M, Roy S, Sen CK: Alpha-lipoic acid supplementation: tissue glutathione homeostasis at rest and after exercise, J Appl Physiol 1999 Apr; 86(4): 1191-6

Aminoglycoside-induced Cochlear Damage

Aminoglycoside-induced Cochlear Damage

This study determined that the free radical scavenger alpha-lipoic acid might attenuate cochlear damage induced by a highly ototoxic regime of the aminoglycoside amikacin. Changes in cochlear function were characterized as shifts in compound action potential (CAP) thresholds. Results showed that animals receiving alpha-lipoic acid in combination with amikacin demonstrated a significantly less severe elevation in CAP thresholds compared with animals receiving amikacin alone. Lipoic acid may potentially be used therapeutically for patients undergoing aminoglycoside treatment.

Conlon BJ, Aran JM, Erre JP, Smith DW: Attenuation of aminoglycoside-induced cochlear damage with the metabolic antioxidant alpha-lipoic acid Hear Res 1999 Feb; 128(1-2): 40-4

Diabetic Peripheral Neuropathy

Diabetic Peripheral Neuropathy

Anti-oxidant treatment has been shown to prevent nerve dysfunction in experimental "diabetes mellitus", thus providing a rationale of potential therapeutic value for "diabetic" patients.

Studied effects of the anti-oxidant alpha-lipoic acid (thioctic acid) in a 3-week multicentre, randomized, double-blind placebo-controlled trial (Alpha-Lipoic Acid in Diabetic Neuropathy; ALADIN) in non-"insulin"-dependent diabetic patients (# 328) with symptomatic peripheral neuropathy.

Subjects were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (I 200, 600, or I 00 mg ALA) or placebo (PLAC).

Neuropathic symptoms ("pain", burning, paraesthesiae, and numbness) were scored at baseline and at each visit (days 2-5, 8-12, and 15-19) prior to infusion.

Total symptom score in the feet decreased from baseline to day 19 by -4.5 +/- 3.7 (-58.6%) points (mean +/- SD) in ALA 1200, -5.0 +/- 4.1 (-63.5%) points in ALA 600, -3.3 +/- 2.8 (-43.2%) points in ALA 100, and -2.6 +/- 3.2 (-3 8.4%) points in PLAC.
Findings substantiate that intravenous treatment with alpha-lipoic acid (using a dose of 600 mg/day over 3 weeks) is superior to placebo in reducing symptoms of diabetic peripheral , neuropathy, without causing significant adverse reactions.

Ziegler D et al: Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 1995 Dec;38(12):1425-33.

Diabetic Polyneuropathy

Diabetic Polyneuropathy

Thioctic (alpha-lipoic) acid (TA) is a drug used for the treatment of diabetic polyneuropathy in Germany. It has been proposed that TA acts as an antioxidant and interferes with the pathogenesis of diabetic polyneuropathy.

One component of its antioxidant activity requiring study is the direct transition metal-chelating activity of the drug.

TA had a profound dose-dependent inhibitory effect upon Cu(2+)-catalysed "ascorbic acid" "oxidation" (monitored by 02 uptake and spectrophotometrically at 265 mu) and also increased the partition of Cu2+ into n-octanol from an aqueous solution suggesting that TA forms a lipophilic complex with Cu2+. TA also inhibited Cu(2+)-catalysed liposomal peroxidation.

Prior "intracellular" reduction of TA to dihydrolipoic acid is not an obligatory mechanism for an antioxidant effect of the drug, which may also operate via Cu(2+)-chelation. The R-enantiomer and racemic mixture of the drug (alpha-TA) generally seemed more effective than the S-enantiomer in these assays of metal chelation.

Ou P et al: Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant? Biochem Pharmacol 1995 Jun 29;50(1):123-6.

Health Benefits

Health Benefits

Clinical studies show that lipoic acid may have the potential to prevent diabetes, influence glucose control, and prevent chronic hyperglycemia associated complications such as neuropathy and cataracts. Lipoic acid may also be useful in the treatment of glaucoma, ischemia-reperfusion injury, mushroom poisoning, and cellular oxidative damage. Therefore, alpha-Lipoic acid is a potent antioxidant in both fat- and water-soluble mediums.

Monograph:Alpha-Lipoic Acid, Altern Med Rev 1998 Aug; 3(4):308-11

Intravenous and Oral Treatments

Intravenous and Oral Treatments

These studies observed that intravenous treatment with alpha-lipoic acid may be effective in reducing symptoms of diabetic peripheral neuropathy, and oral treatment may improve cardiac autonomic dysfunction in NIDDM. The effects of alpha-lipoic acid were experimented in double-blinded placebo-controlled trials. Over three hundred patients with NIDDM and symptomatic peripheral neuropathy were treated with intravenous infusion of alpha-lipoic acid or placebo during the trial. The results showed that the patients' symptoms, including pain, burning, paresthesia and numbness decreased with alpha-lipoic acid compared to placebo. Alpha-lipoic acid may decrease the symptoms of diabetic peripheral and cardiac autonomic neuropathy.

Ziegler D, Gries FA: Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy, Diabetes 1997 Sep; 46 Supp l 2:S62-6

Lens Damage Protection

Lens Damage Protection

This study confirmed that antioxidants, including R-alpha-lipoic acid, and cysteine precursor drugs, might protect the lens from low level gamma radiation. Tocopherol, ascorbic acid, R-alpha-lipoic acid, and taurine could protect the lens against radiation-associated protein leakage. These results provided that the drugs and antioxidants might be beneficial to astronauts, jet crews and military radiation accident personnel who might be at risk for radiation exposure.

Bantseev V, Bhardwaj R, Rathbun W, Nagasawa H, Trevithick JR: Antioxidants and cataract: (cataract induction in space environment and application to terrestrial aging cataract), Biochem Mol Biol Int 1997 Sep; 42 (6): 1189-97

Therapeutic Potential

Therapeutic Potential

Lipoic acid may have therapeutic potential in conditions caused by oxidative stress. These studies have indicated R-alpha Lipoic acid has an important role in cellular metabolism. Alpha-lipoic acid was used as a therapeutic agent for liver disease caused by alcohol damage, mushroom poisoning, metal intoxication, and CCl4 poisoning. This supplementation was successful in the treatment for these conditions in many cases. These results may encourage health professionals to use alpha-lipoic acid in liver diseases due to oxidative stress.

Bustamante J, Lodge JK, Marcocci L, Tritschler HJ, Packer L, Rihn BH: Alpha-lipoic acid in liver metabolism and disease, Free Radic Biol Med 1998 Apr; 24(6): 1023-39

Type 2 Diabetes

Type 2 Diabetes

Lipoic acid (LA) used in treating lean and obese diabetic patients may prevent an increase in lactate and pyruvate levels due to hyperglycemia and may increase glucose effectiveness. Lactate and pyruvate before and after glucose ingestion were approximately 45% lower in both lean and obese diabetic patients after LA treatment. Alpha-lipoic acid may increase glucose effectiveness among diabetic patients.

Konrad T, Vicini P, Kusterer K, Hoflich A, Assadkhani A, Bohles HJ, Sewell A, Tritschler HJ, Cobelli C, Usadel KH: alpha-Lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes, Diabetes Care 1999 Feb; 22(2): 280-7

Diabetic Kidney Damage

Diabetic Kidney Damage

Supplementation with lipoic acid may prevent early diabetes-related kidney damage, according to this animal study. For two months, diabetic rats were fed either unsupplemented diets, or diets supplemented with lipoic acid, vitamin E, or vitamin C. Researchers tested the effects of supplementation through six parameters - all parameters that were significantly increased in diabetic rats compared with controls, and that are associated with kidney damage. Lipoic acid appeared to prevent increases in five out of six parameters. Lipoic acid also significantly increased the kidney's content of glutathione, an enzyme that may be deficient in diabetics.

Melhem MF, Craven PA, Derubertis FR: Effects of Dietary Supplementation of alpha-Lipoic Acid on Early Glomerular Injury in Diabetes Mellitus, J Am Soc Nephrol 2001 Jan;12(1):124-133

Diabetes & Alpha-lipoic Acid

Diabetes

Alpha-lipoic acid may help to reduce oxidative stress associated with diabetic kidney disease, according to this open, prospective study on 84 diabetic patients with urinary albumin concentration less than 200 mg/l. Subjects were treated with either 600 mg alpha-lipoic acid daily, or nothing. After 18 months of treatment, patients who received alpha-lipoic acid experienced decreased plasma thrombomodulin levels, whereas thrombomodulin levels increased in untreated patients. The untreated group also exhibited increases in urinary albumin concentration, but supplementation with alpha-lipoic acid caused urinary albumin excretion to remain unchanged from baseline.

Morcos M, et al: Effect of alpha-lipoic acid on the progression of endothelial cell damage and albuminuria in patients with diabetes mellitus: an exploratory study, Diabetes Res Clin Pract 2001 Jun;52(3):175-83

Memory Loss

Memory Loss

A combination of R-alpha lipoic acid (LA) and acetyl-L-carnitine (ALCAR) may reduce oxidative damage to mitochondria that are vital to memory function in the brain, according to this study on older rats. Spatial memory and temporal memory were assessed in the rats using the Morris water maze and the peak procedure, respectively. The rats were fed LA and/or ALCAR, which are mitochondrial metabolites, to see if the supplements improved their memory. An immunohistochemical analysis found that oxidative damage primarily occurred in the RNA of the hippocampal cells, and that dietary administration of LA and/or ALCAR significantly reduced this damage. The combination of the two proved to be the most effective way to prevent the effects of oxidation. It was also found that the supplements reversed age-associated structural damage of mitochondria.

Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, Ames BN: 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, Proc Natl Acad Sci USA 2002 Feb 19;99(4):2356-61

 


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