Lipoic Acid. Anti-Aging-Guide -- Your plan to stay young

J Clin Pharmacol. 2005 Mar;45(3):313-28.
Pharmacokinetics of alpha-lipoic Acid in subjects with severe kidney damage and end-stage renal disease.
Teichert J, Tuemmers T, Achenbach H, Preiss C, Hermann R, Ruus P, Preiss R.
University of Leipzig, Institute of Clinical Pharmacology, Hartelstr. 16-18, 04107 Leipzig, Germany.
In an open-label, parallel-group study involving 16 patients (8 with severely reduced renal function, 8 with end-stage renal disease needing hemodialysis), the effect of renal function on the pharmacokinetics, metabolism, and safety and of alpha-lipoic acid (thioctic acid) was evaluated by comparing the pharmacokinetic parameters with those of a reference group of 8 healthy subjects. Alpha-lipoic acid 600 mg was administered orally once daily for 4 days, and the pharmacokinetic parameters were measured on days 1 and 4. The mean percentage of the administered dose excreted in urine as parent compound was 0.2 and 0.05 in healthy subjects and subjects with severely reduced renal function, respectively. Assuming a bioavailability of 30%, this represents 0.67% and 0.17% of the bioavailable amount of alpha-lipoic acid, respectively. The percentage of total urinary recovered amounts of alpha-lipoic acid and 5 of its metabolites was 12.0 on both days. The respective values for patients with severe kidney damage were 5.2% (day 1) and 6.4% (day 4). The total percentage of the administered dose removed by hemodialysis was 4.0 in patients with end-stage renal disease. Renal clearance of alpha-lipoic acid and its major metabolites, 6,8-bismethylthio-octanoic acid, 4,6-bismethylthio-hexanoic acid and 2,4-bismethylthio-butanoic acid, were significantly decreased in subjects with kidney damage compared to the reference group. Apparent total clearance of alpha-lipoic acid was poorly correlated with creatinine clearance. There is strong evidence that alpha-lipoic acid is mainly excreted by nonrenal mechanism or further degraded to smaller units in the catabolic process. The significantly increased area under the curve values of 4,6-bismethylthio-hexanoic acid and half-lives of 2,4-bismethylthio-butanoic acid on both days in patients with severely reduced function and end-stage renal disease were not considered to be clinically relevant. Although trough levels of both metabolites tend to increase slightly in these subjects, no accumulation effects were detected. We conclude that the pharmacokinetics of alpha-lipoic acid are not influenced by creatinine clearance and are unaffected in subjects with severely reduced kidney function or end-stage renal disease. Hemodialysis did not significantly contribute to the clearance of alpha-lipoic acid. Hence, dose adjustment of alpha-lipoic acid is not necessary in patients with renal dysfunction.

Ageing Res Rev. 2004 Jul;3(3):303-18.
Heme, iron, and the mitochondrial decay of ageing.
Atamna H.
Childrens Hospital Oakland Research Institute (CHORI), 5700 Martin Luther King Jr. Way, Oakland, CA 94609-1673, USA.
Heme, the major functional form of iron, is synthesized in the mitochondria. Although disturbed heme metabolism causes mitochondrial decay, oxidative stress, and iron accumulation, all of which are hallmarks of ageing, heme has been little studied in nutritional deficiency, in ageing, or age-related disorders such as Alzheimer's disease (AD). Biosynthesis of heme requires Vitamin B(6), riboflavin, biotin, pantothenic acid, and lipoic acid and the minerals zinc, iron, and copper, micronutrients are essential for the production of succinyl-CoA, the precursor for porphyrins, by the TCA (Krebs) cycle. Only a small fraction of the porphyrins synthesized from succinyl-CoA are converted to heme, the rest are excreted out of the body together with the degradation products of heme (e.g. bilirubin). Therefore, the heme biosynthetic pathway causes a net loss of succinyl-CoA from the TCA cycle. The mitochondrial pool of succinyl-CoA may limit heme biosynthesis in deficiencies for micronutrients (e.g. iron or biotin deficiency). Ageing and AD are also associated with hypometabolism, increase in heme oxygenase-1, loss of complex IV, and iron accumulation. Heme is a common denominator for all these changes, suggesting that heme metabolism maybe altered in age-related disorders. Heme can also be a prooxidant: it converts less reactive oxidants to highly reactive free radicals. Free heme has high affinity for different cell structures (protein, membranes, and DNA), triggering site-directed oxidative damage. This review discusses heme metabolism as related to metabolic changes seen in ageing and age-related disorders and highlights the possible role in iron deficiency.

Arch Dermatol Res. 2004 Jun 24 [Epub ahead of print]
alpha-Lipoic acid-based PPARgamma agonists for treating inflammatory skin diseases.
Venkatraman MS, Chittiboyina A, Meingassner J, Ho CI, Varani J, Ellis CN, Avery MA, Pershadsingh HA, Kurtz TW, Benson SC.
Department Medicinal Chemistry, University of Mississippi, University, MS, USA.
Novel thiazolidinedione derivatives of the potent antioxidant, alpha-lipoic (thioctic, 1,2-dithiolane) acid, were prepared. The prototype N-(2-{4-[2,4-dioxo(1,3-thiazolidin-5-yl)methyl]phenoxy}ethyl)-5-(1,2-dithiolan-3-yl)- N-methylpentanamide (designated BP-1003), and dithioester derivatives thereof were shown to be potent activators of peroxisome proliferator-activated receptor gamma (PPARgamma) (EC(50) range 15-101 n M) and modest activators of PPARalpha (EC(50) 5 micro M). Both the relatively hydrophobic dithiolane prototype, BP-1003, and its water-soluble dithioglycinate derivative, BP-1017, were shown to inhibit the proliferation of human keratinocytes and suppress the production of interleukin-2 by human peripheral lymphocytes to a greater extent than the antidiabetic thiazolidinedione, rosiglitazone. Both oral and topical administration of BP-1017 showed significant antiinflammatory effects in the oxazolone-sensitized mouse model of allergic contact dermatitis (ACD). These findings suggest that water-soluble lipoic acid-based thiazolidinediones may be efficacious as oral and topical agents for treating inflammatory skin conditions such as contact dermatitis, atopic dermatitis, and psoriasis.

Chem Biol Interact. 2004 Apr 15;147(3):259-71.
Therapeutic efficacy of lipoic acid in combination with dimercaptosuccinic acid against lead-induced renal tubular defects and on isolated brush-border enzyme activities.
Sivaprasad TR, Malarkodi SP, Varalakshmi P.
Department of Medical Biochemistry, Dr. A.L.M. PGIBMS, University of Madras, Taramani Campus, Chennai 600113, India.
The combined therapeutic potentials of lipoic acid and dimercaptosuccinic acid were compared against their sole administrations in restoring the altered lead sensitive indices in urine and isolated renal brush-border preparations. Toxicity was induced in male albino rats (Wistar strain) by administering lead acetate (0.2%) in drinking water for 5 weeks, followed by therapy comprising lipoic acid (25 mg/kg body weight) and dimercaptosuccinic acid (20 mg/kg body weight) solely as well as combined during the 6th week. Changes in kidney weights encountered upon lead administration improved after therapy with lipoic acid and dimercaptosuccinic acid. Renal integrity was assessed by measuring the activities of alkaline phosphatase, acid phosphatase, lactate dehydrogenase, leucine aminopeptidase, N-acetyl-beta-D-glucosaminidase, gamma-glutamyl transferase and beta-glucuronidase in urine along with some urinary constituents (urea, uric acid, creatinine, protein and phosphorous). The effects of lead were also studied on isolated brush-border enzymes (alkaline phosphatase, acid phosphatase, gamma-glutamyl transferase and beta-glucuronidase) that showed a decline upon its administration. Increased activities of urinary enzymes were accompanied by increase in the urinary constituents. Increase in renal lead content was paralleled by a drastic fall in the renal delta-aminolevulinic acid dehydratase and a rise in urinary lead levels. Relative to the administration of lead, the combined therapy showed betterment on the renal integrity with respect to the functional parameters assessed, thereby indicating its efficacy over the monotherapies.

Curr Med Chem. 2004 May;11(9):1135-46.
Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress.
Smith AR, Shenvi SV, Widlansky M, Suh JH, Hagen TM.
Dept. of Biochemistry and Biophysics and the Linus Pauling Institute, 571 Weniger Hall, Oregon State University, Corvallis, Oregon 97331, USA.
alpha-Lipoic acid (LA), a naturally occurring dithiol compound, has long been known as an essential cofactor for mitochondrial bioenergetic enzymes. Aside from its enzymatic role, in vitro and in vivo studies suggest that LA also acts as a powerful micronutrient with diverse pharmacologic and antioxidant properties. Pharmacologically, LA improves glycemic control, polyneuropathies associated with diabetes mellitus, and effectively mitigates toxicities associated with heavy metal poisoning. As an antioxidant, LA directly terminates free radicals, chelates transition metal ions (e.g. iron and copper), increases cytosolic glutathione and vitamin C levels and prevents toxicities associated with their loss. These diverse actions suggest that LA acts by multiple mechanisms both physiologically and pharmacologically, many of which are only now being explored. Herein, we review the known biochemical properties of LA with particular reference to how LA may be an effective agent to ameliorate certain pathophysiologies of many chronic diseases.

Plant Physiol Biochem. 2004 Apr;42(4):329-34.
The role of lipoic acid in the regulation of the redox status of wheat irrigated with 20% sea water.
DAmico ML, Navari-Izzo F, Sgherri C, Izzo R.
Dipartimento di Chimica e Biotecnologie Agrarie, Via del Borghetto, 80-56124 Pisa, Italy.
The effect of irrigation with 20% sea water was studied in 14 and 21-day-old seedlings of durum wheat (Triticum durum, cv. Ofanto). Comparisons between control (Hoagland's 2 solution) and treated (20% sea water in Hoagland's solution) plants included, besides HPLC determination of reduced (DHLA) and oxidised (LA) forms of lipoic acid, ascorbate and glutathione contents, their redox status, the activity of ascorbate peroxidase (APX, EC 1.11.1.11.) and glutathione reductase (GR, EC 1.6.4.2.). The results indicated a more relevant presence of lipoic acid in the roots in comparison to the shoots. An involvement of its reduced form in the regeneration of the reduced glutathione, at least at 14 days of treatment, suggested, besides its role as dehydrogenase enzyme cofactor, a role in the recycling of the other antioxidants. The amount of LA always increased with growth in shoots and decreased in roots, while DHLA remained constant in control and increased in treated plants. Besides, the oxidised form always decreased with sea water while the reduced form decreased in shoots and increased in roots. The ascorbate pool exerted its positive influence especially in the shoots, while APX and GR activities resulted differently modulated by the salinity level.

Diabet Med. 2004 Feb;21(2):114-21.
Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis.
Ziegler D, Nowak H, Kempler P, Vargha P, Low PA.
German Diabetes Research Institute, Leibriz Institute at the Heinrich Heine University, Dusseldorf, Germany.
AIMS: To determine the efficacy and safety of 600 mg of alpha-lipoic acid given intravenously over 3 weeks in diabetic patients with symptomatic polyneuropathy. METHODS: We searched the database of VIATRIS GmbH, Frankfurt, Germany, for clinical trials of alpha-lipoic acid according to the following prerequisites: randomized, double-masked, placebo-controlled, parallel-group trial using alpha-lipoic acid infusions of 600 mg i.v. per day for 3 weeks, except for weekends, in diabetic patients with positive sensory symptoms of polyneuropathy which were scored by the Total Symptom Score (TSS) in the feet on a daily basis. Four trials (ALADIN I, ALADIN III, SYDNEY, NATHAN II) comprised n=1258 patients (alpha-lipoic acid n=716; placebo n=542) met these eligibility criteria and were included in a meta-analysis based on the intention-to-treat principle. Primary analysis involved a comparison of the differences in TSS from baseline to the end of i.v. Treatment between the groups treated with alpha-lipoic acid or placebo. Secondary analyses included daily changes in TSS, responder rates (> or =50% improvement in TSS), individual TSS components, Neuropathy Impairment Score (NIS), NIS of the lower limbs (NIS-LL), individual NIS-LL components, and the rates of adverse events. RESULTS: After 3 weeks the relative difference in favour of alpha-lipoic acid vs. placebo was 24.1% (13.5, 33.4) (geometric mean with 95% confidence interval) for TSS and 16.0% (5.7, 25.2) for NIS-LL. The responder rates were 52.7% in patients treated with alpha-lipoic acid and 36.9% in those on placebo (P<0.05). On a daily basis there was a continuous increase in the magnitude of TSS improvement in favour of alpha-lipoic acid vs. placebo which was noted first after 8 days of treatment. Among the individual components of the TSS, pain, burning, and numbness decreased in favour of alpha-lipoic acid compared with placebo, while among the NIS-LL components pin-prick and touch-pressure sensation as well as ankle reflexes were improved in favour of alpha-lipoic acid after 3 weeks. The rates of adverse events did not differ between the groups. CONCLUSIONS: The results of this meta-analysis provide evidence that treatment with alpha-lipoic acid (600 mg/day i.v.) over 3 weeks is safe and significantly improves both positive neuropathic symptoms and neuropathic deficits to a clinically meaningful degree in diabetic patients with symptomatic polyneuropathy.

J Neuroimmunol. 2004 Mar;148(1-2):146-53.
Alpha-lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis.
Morini M, Roccatagliata L, Dell'Eva R, Pedemonte E, Furlan R, Minghelli S, Giunti D, Pfeffer U, Marchese M, Noonan D, Mancardi G, Albini A, Uccelli A.
Molecular Oncology Laboratory, National Cancer Research Institute, Genoa, Italy.
Alpha-lipoic acid (alpha-LA) is a neuroprotective metabolic antioxidant that has been shown to cross the blood brain barrier. We tested whether alpha-LA is capable to prevent MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis (MS). Daily oral administration of alpha-LA, starting at the time of immunization, significantly prevented EAE progression as compared to control mice. This was associated with a reduction of CNS infiltrating T cells and macrophages as well as decreased demyelination. We then tested alpha-LA in a therapeutic protocol aimed at suppressing EAE after its onset. Intraperitoneal (i.p.), but not oral, administration of alpha-LA significantly prevented disease progression when compared to vehicle-treated controls. Similarly, we observed significant reduction of demyelination and inflammatory infiltration. This clinical effect was not due to an impairment of MOG35-55 recognition by encephalitogenic T cells. In contrast, MOG-specific T cells showed a decreased production of IFNgamma and IL-4, suggesting an immunosuppressive activity on both Th1 and Th2 cytokines. In addition, alpha-LA inhibited the proteolytic activity of MMP2 and MMP9 only at very high doses. Our data indicate that alpha-LA can effectively interfere with the autoimmune reaction associated with EAE through mechanisms other than its antioxidant activity and supports further studies on the use of alpha-LA as a potential therapy for MS.

Cochrane Database Syst Rev. 2004;(1):CD004244.
Alpha lipoic acid for dementia.
Sauer J, Tabet N, Howard R.
Section of Old Age Psychiatry, Institute of Psychiatry, De Crespigny Park, London, UK, SE5 8AF.
BACKGROUND: Oxidative processes have been implicated in the pathogenesis of neurodegenerative dementias including Alzheimer's disease. Protecting the central nervous system against these damaging mechanisms may be a useful therapeutic approach. Alpha lipoic acid (ALA) is an endogenous antioxidant that interrupts cellular oxidative processes in both its oxidized and reduced forms. These properties might qualify ALA for a modulatory role in the treatment of people with dementia. OBJECTIVES: To assess the role and clinical efficacy of alpha lipoic acid in the treatment of dementia. SEARCH STRATEGY: A search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG) on 3 February 2003 using the terms 'alpha lipoic acid' and 'thioctic'. The CDCIG Specialized register is updated regularly and contains records from all major health care databases (MEDLINE, EMBASE, PsycInfo, CINAHL) as well as from many trials databases. SELECTION CRITERIA: All double-blind randomized placebo-controlled trials examining the efficacy of alpha lipoic acid in dementia DATA COLLECTION AND ANALYSIS: No trials were found that met the selection criteria MAIN RESULTS: No meta-analysis could be performed. A systematic search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, as well as registers of ongoing and unpublished trials could not identify any studies investigating the use of ALA for dementia. REVIEWER'S CONCLUSIONS: In the absence of randomized double-blind placebo-controlled trials investigating ALA for dementia, no evidence exists to explore any potential effects. Until data from trials become available for analysis, ALA cannot be recommended for people with dementia.

J Biol Chem. 2004 Mar 12;279(11):9693-7. Epub 2003 Dec 29.
Lipoic acid protects efficiently only against a specific form of peroxynitrite-induced damage.
Rezk BM, Haenen GR, van der Vijgh WJ, Bast A.
Department of Pharmacology and Toxicology, Faculty of Medicine, Universiteit Maastricht, The Netherlands.
The ability of the sulfur-containing compounds glutathione (GSH), glutathione disulphide (GSSG), S-methylglutathione (GSMe), lipoic acid (LA), and dihydrolipoic acid (DHLA) to protect against hypochlorous acid (HOCl)-mediated damage and peroxynitrite (ONOOH)-induced damage has been compared. Protective activity was assessed in competition assays by monitoring several detectors, i.e. dihydrorhodamine-123 (DHR-123) oxidation, alpha(1)-antiproteinase (alpha(1)-AP) inactivation, and glutathione S-transferase P1-1 (GST-P1-1) inactivation. In addition, nitration of tyrosine was measured to assess protection of the sulfur-containing compounds against ONOOH. For protection against HOCl, the efficacy of the antioxidant was controlled by the ratio of the reaction rates of the antioxidant and the detector molecule with the oxidant. The rank order of the activity of the antioxidants (GSH > DHLA approximately LA approximately GSMe > GSSG) appeared to be independent of the detector used. However, the rank order of the antioxidants against ONOOH-induced damage is strongly dependent on the detector. LA was 40 times less active than GSH in the inhibition of ONOOH-induced DHR-123 oxidation, whereas LA was 20 times more active than GSH in preventing the inhibition of GST-P1-1 by ONOOH. This points to different molecular mechanisms of ONOOH damage to DHR-123 compared with ONOOH damage to GST-P1-1. LA is a poor antioxidant in protecting against the form of ONOOH damage involved in DHR-123 oxidation. In the form of ONOOH toxicity involved in GST-P1-1 inhibition, LA is the most potent sulfur-containing antioxidant in our series. It is proposed that an intermediate product in which both sulfur atoms of LA have reacted is involved in the reaction of ONOOH with LA. The high potency of LA to protect GST-P1-1 against ONOOH might be of therapeutic interest.

Avian Pathol. 2003 Dec;32(6):645-53.
Prophylactic action of lipoic acid on oxidative stress and growth performance in broilers at risk of developing ascites syndrome.
Diaz-Cruz A, Serret M, Ramirez G, Avila E, Guinzberg R, Pina E.
Department of Animal Nutrition and Biochemistry, Faculty of Veterinary Medicine and Zootechnics, National Autonomous University of Mexico, Mexico.
The objective of this study was to assess the effects of dietary supplementation with lipoic acid (LA) on broilers maintained at 2235 m above sea level with high risk to develop ascites syndrome (AS). A total of 2040 chicks were fed under commercial conditions with water and specific diets ad libitum during 7 weeks in two consecutive experiments. Mortality and indicators of performance and oxidative stress were compared weekly in broilers fed a basal diet plus 0, 10, 20, or 40 parts/10(6) LA. The effects of LA at 40 parts/10(6) were also studied during the initial 3 weeks or the last 4 weeks of the production cycle. Diets supplemented with 40 parts/10(6) of LA during 7 weeks significantly improved feed conversion, decreased general mortality and mortality attributable to AS, and lowered thiobarbituric acid reactive substances and hydroxyl radicals in liver, and increased total glutathione pool. Smaller doses or shorter periods of exposure to LA were partially effective. In conclusion, LA under our experimental conditions has a prophylactic action in broilers with high risk to develop AS due to oxygen availability limitation.

Toxicol In Vitro. 2003 Oct-Dec;17(5-6):753-9.
Protective effect of lipoic acid against hydrogen peroxide in yeast cells.
Della Croce C, Bronzetti G, Cini M, Caltavuturo L, Poi G.
Institute of Biology and Agricultural Biotechnology (IBBA), CNR Research Area, Via Moruzzi, 56124 Pisa, Italy.
Lipoic acid (LA) is found in all kinds of cells, it is widely used in medicine and as a dietary supplement, and it is involved in different physiological functions. Even if there are many papers regarding therapeutic effects of LA, medical research does not always support its effectiveness and little is known about LA metabolism in eukaryotic cells. In this work the probable protective effect of LA was investigated employing five strains of yeast Saccharomyces cerevisiae through short term assays. In particular LA behaviour in oxidative stress conditions was studied. For this purpose hydrogen peroxide was used as oxidant. In D7 strain, LA showed antimutagenic effects against hydrogen peroxide and decreased significantly cytochrome P450. To better elucidate the effect of LA the following yeast strains carrying deletions in superoxide dismutase genes (SOD) were employed: EG-103 (wild type), EG-110 strain (without mytochondrial SOD), EG-118 (without cytoplasmatic SOD) and EG-133 (without both enzymes). LA increased the number of mitotic divisions in EG-103, EG-110 and EG-133 and in growing cells (EG-103, EG-110, EG-118) it increased survival percentage with respect to hydrogen peroxide. The positive action was evident in D7 and in EG strains and it showed that LA can be protective and antimutagenic against oxidants in yeast cells, via its antioxidant activity.

Arch Environ Health. 2003 Aug;58(8):528-32.
Lipoic acid as a potential first agent for protection from mycotoxins and treatment of mycotoxicosis.
Rogers SA.
Northeast Center for Environmental Medicine, Sarasota, Florida, USA.
Mycotoxins--toxic substances produced by fungi or molds--are ubiquitous in the environment and are capable of damaging multiple biochemical mechanisms, resulting in a variety of human symptoms referred to collectively as "mycotoxicosis." In fact, mycotoxins mimic multiple xenobiotics, not only with respect to their ultimate damage, but also in their routes of detoxification. This suggests potential therapeutic options for the challenging treatment of mycotoxicosis. In this brief review, the author examines the use of lipoic acid as an example of an inexpensive and available nutrient that has been shown to protect against, or reverse, the adverse health effects of mycotoxins.