Alpha lipoic acid intoxication, treatment and outcome

Regulatory Toxicology and Pharmacology, 2006

Lipoic acid (ALA) (CAS RN 1077-28-7), also referred to as thioctic acid, has been demonstrated to exhibit strong anti-oxidant properties. In order to test the long-term toxicity of ALA, groups of 40-50 male and female, 5-6-week-old, Sprague-Dawley rats were subjected to oral administration of 20, 60, or 180 mg/kg body weight (bw)/day ALA for 24 months. There was no signiWcant diVerence between control animals and treated animals at 20 or 60 mg/kg bw/day with respect to body weight gain, food consumption, behavioural eVects, haematological and clinical chemistry parameters, and gross and histopathological Wndings. In all treatment groups, mortality was slightly lower as compared to the control. The absolute weights of the heart (high-dose males), thymus (high-dose males), and left adrenal (mid-dose males), liver (high-dose females), and lungs (high-dose females) were decreased in comparison to controls. These changes were of no toxicological signiWcance. The only notable Wnding in rats of both sexes dosed at 180 mg/kg bw/day was a reduction in food intake relative to the controls and a concomitant decrease in body weight. This decrease in body weight led to signiWcant diVerences between the control and high-dose rats with respect to the absolute weights of certain organs. However, no gross or histopathological changes were associated with these Wndings. The no-observed-adverse-eVect level (NOAEL) is considered to be 60 mg/kg bw/day.

Molecular and Cellular Biochemistry, 2010

N-Acetylaspartic acid (NAA) accumulates in Canavan disease, a severe inherited neurometabolic disorder clinically characterized by mental retardation, hypotonia, macrocephaly, and seizures. The mechanisms of brain damage in this disease remain poorly understood. Recent studies developed by our research group showed that NAA induces oxidative stress in vitro and in vivo in cerebral cortex of rats. Lipoic acid is considered as an efficient antioxidant which can easily cross the blood–brain barrier. Considering the absence of specific treatment to Canavan disease, this study evaluates the possible prevention of the oxidative stress promoted by NAA in vivo by the antioxidant lipoic acid to preliminarily evaluate lipoic acid efficacy against pro-oxidative effects of NAA. Fourteen-day-old Wistar rats received an acute administration of 0.6 mmol NAA/g body weight with or without lipoic acid (40 mg/kg body weight). Catalase (CAT), glutathione peroxidase (GPx), and glucose 6-phosphate dehydrogenase activities, hydrogen peroxide content, thiobarbituric acid-reactive substances (TBA-RS), spontaneous chemiluminescence, protein carbonyl content, total antioxidant potential, and DNA–protein cross-links were assayed in the cerebral cortex of rats. CAT, GPx activities, and total antioxidant potential were significantly reduced, while hydrogen peroxide content, TBA-RS, spontaneous chemiluminescence, and protein carbonyl content were significantly enhanced by acute administration of NAA. Those effects were all prevented by lipoic acid pretreatment. Our results clearly show that lipoic acid may protect against the oxidative stress promoted by NAA. This could represent a new therapeutic approach to the patients affected by Canavan disease.

1997

α− Lipoic acid is unique in its ability to act as an antioxidant in fat- and watersoluble tissues in both its oxidized and reduced forms. It is readily absorbed from an oral dose. Because of its myriad biological activities, including an ability to chelate metals and to scavenge a wide array of free radicals, α− lipoic acid is considered by several experts to be an ideal antioxidant. Clinical applications for this nutrient include the following conditions: diabetic polyneuropathy, cataracts, glaucoma, ischemia− reperfusion injury, and Amanita mushroom poisoning. Because of its unique characteristics α− lipoic acid is likely to have therapeutic application in a wide range of additional clinical conditions. (Alt Med Rev 1997; 2(3):177-183)

Clinical and Experimental Pharmacology and Physiology, 2002

Background: Long term administration of antiepileptic drug phenytoin is reported to cause behavioral abnormalities mediated via oxidative stress. The effect of an antioxidant alpha lipoic acid (ALA) against phenytoin induced behavioral abnormalities was investigated. Methods: The study was carried out in albino wistar rats. The rats were divided into five groups of six animals each. Group 1 received 0.2% carboxy methyl cellulose (CMC, p.o), group 2 received 20 mg/kg phenytoin (p.o), groups 3,4 and 5 received 50, 100 and 200 mg/kg (p.o) of ALA in 0.2% CMC, respectively 1 h prior to phenytoin for 45 days. Motor coordination, exploratory behavior, memory and spontaneous motor activity were evaluated by Rota rod, Hole board, Elevated plus maze and Actophotometer respectively. On day 45, regional brain lipid peroxidation and acetylcholinesterase (ACh E) activity along with brain histopathological investigation were performed after euthanasia. In addition, pharmacokinetic and pharmacodynamic drug interactions between phenytoin and ALA were also studied. Results: Long term administration of phenytoin showed behavioral abnormalities, increased regional brain malondialdehyde (MDA) and ACh E activity. The histopathological investigation showed congested and damaged cells in brain regions. ALA substantially reversed phenytoin induced behavioral abnormalities, oxidative stress and alleviated the histopathological abnormalities. There were no significant differences in the serum levels of phenytoin and the degree of protection offered by phenytoin in ALA supplemented groups revealing that there were no pharmacokinetic and pharmacodynamic interactions between phenytoin and ALA. Conclusion: This study reports the effectiveness of ALA against phenytoin induced behavioral abnormalities and oxidative stress in rats without altering the bioavailability of phenytoin and its therapeutic effect.

Diabetology & Metabolic Syndrome, 2014

Alpha-lipoic acid is a naturally occurring substance, essential for the function of different enzymes that take part in mitochondria's oxidative metabolism. It is believed that alpha-lipoic acid or its reduced form, dihydrolipoic acid have many biochemical functions acting as biological antioxidants, as metal chelators, reducers of the oxidized forms of other antioxidant agents such as vitamin C and E, and modulator of the signaling transduction of several pathways. These above-mentioned actions have been shown in experimental studies emphasizing the use of alpha-lipoic acid as a potential therapeutic agent for many chronic diseases with great epidemiological as well economic and social impact such as brain diseases and cognitive dysfunctions like Alzheimer disease, obesity, nonalcoholic fatty liver disease, burning mouth syndrome, cardiovascular disease, hypertension, some types of cancer, glaucoma and osteoporosis. Many conflicting data have been found concerning the clinical use of alpha-lipoic acid in the treatment of diabetes and of diabetes-related chronic complications such as retinopathy, nephropathy, neuropathy, wound healing and diabetic cardiovascular autonomic neuropathy. The most frequent clinical condition in which alpha-lipoic acid has been studied was in the management of diabetic peripheral neuropathy in patients with type 1 as well type 2 diabetes. Considering that oxidative stress, a imbalance between pro and antioxidants with excessive production of reactive oxygen species, is a factor in the development of many diseases and that alpha-lipoic acid, a natural thiol antioxidant, has been shown to have beneficial effects on oxidative stress parameters in various tissues we wrote this article in order to make an up-to-date review of current thinking regarding alpha-lipoic acid and its use as an antioxidant drug therapy for a myriad of diseases that could have potential benefits from its use.

The Review of Diabetic …, 2009

Diabetic neuropathy presents a major public health problem. It is defined by the symptoms and signs of peripheral nerve dysfunction in diabetic patients, in whom other causes of neuropathy have been excluded. Pathogenetic mechanisms that have been implicated in diabetic neuropathy are: a) increased flux through the polyol pathway, leading to accumulation of sorbitol, a reduction in myo-inositol, and an associated reduced Na+-K+-ATPase activity, and b) endoneurial microvascular damage and hypoxia due to nitric oxide inactivation by increased oxygen free radical activity. Alpha-lipoic acid seems to delay or reverse peripheral diabetic neuropathy through its multiple antioxidant properties. Treatment with alpha-lipoic acid increases reduced glutathione, an important endogenous antioxidant. In clinical trials, 600 mg alpha-lipoic acid has been shown to improve neuropathic deficits. This review focuses on the relationship of alpha-lipoic acid and auto-oxidative glycosylation. It discusses the impact of alpha-lipoic acid on hyperglycemia-induced oxidative stress, and examines the role of alpha-lipoic acid in preventing glycation process and nerve hypoxia.

Journal of Physiology and Biochemistry, 2013

Alpha-lipoic acid (ALA) is widely used as an antioxidant for the treatment of diabetes and its complications; however, the pro-oxidant potential of ALA has recently been reported. This study was designed to investigate whether ALA supplementation could have pro-oxidant effects on cardiac tissues in normal and diabetic rats. Diabetes was induced by a single dose of streptozotocin (STZ; 55 mg/kg (intraperitoneal). Diabetic and normal rats were treated with ALA (100 mg kg −1 day −1 ) for 45 days. ALA supplementation resulted in oxidative protein damage as evident by significant reduction in the cardiac levels of protein thiol in ALA-treated normal rats (P<0.01) together with a significant elevation (P<0.001) in the plasma levels of advanced oxidation protein products in ALA-treated normal rats and in ALA+STZ-diabetic rats compared with the normal control rats. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has emerged as the major source of superoxide anion and enhanced oxidative damage in heart failure. ALA supplementation increased the myocardial immunoreactivity of p47phox subunit of NADPH oxidase in both normal nondiabetic and diabetic rats reflecting its pro-oxidant effect. Data showed that ALA supplementation failed to prevent cardiac complications in diabetic rats and led to cardiac toxicity in normal rats as indicated by pathological changes (cellular infiltration, fibrosis, and degeneration) and by the elevation of serum cardiac biomarkers compared with normal controls. The pro-oxidant effects of ALA suggest that careful selection of appropriate doses of ALA in reactive oxygen species-related diseases are critical.

ABSTRACT Alpha lipoic acid (ALA, thioctic acid), among other actions, is an essential coenzyme in the conversion of pyruvate to acetyl co-enzyme A. Therefore, it is necessary for the production of energy for aerobic organisms. Scientists have found that it can be used medically to help regenerate liver tissue, reverse the complications of diabetes mellitus, slow or stop the growth of cancer cells, and chelate heavy metals, among other actions. In this article, the authors describe the cellular mitochondrial damage from excessively high doses of this beneficial agent

Arquivos de Neuro-Psiquiatria, 2003

Oxidative stress causes metabolic and structural abnormalities during reperfusion. In an animal model of electrophysiological evaluation of cerebral ischemia-reperfusion, α-lipoic acid effect on the oxidative stress was studied by mean absolute amplitude of EEG spectra evaluation. The left carotideal infusion of 3.03 mM α-lipoic acid in Wistar rats after cerebral ischemia and reperfusion caused initial reduction and partial final recuperation of the various EEG spectral frequency mean absolute amplitudes (p<0.05). The left intracarotideal infusion of 6.06 mM α-lipoic acid significantly reverted the induced depression of mean absolute amplitude of theta and delta spectra. Nevertheless there was an increasing pattern of ischemia demonstrated by mean absolute amplitude depression of almost all EEG spectra with 60.6 mM α-lipoic acid infusion. These observations suggest that, depending on the administered concentration, α-lipoic acid may act in a dual way, protecting from ischemia at lower concentrations and worsening this process at higher doses.

Balkan Medical Journal, 2013

Background: Oxidative stress is believed to be an important factor in the pathogenesis of acute lung injury (ALI). Aims: The aim of this study was to investigate the possible protective role of alpha-lipoic acid (α-LA) on oleic acid (OA)-induced ALI in rats. Study Design: Animal experiment. Methods: A total of thirty-five rats were divided into five groups in the study. Group 1 served as a control group. Rats in Group 2 (α-LA) were administered α-LA intraperitoneally at a dose of 100 mg/kg body weight (BW). Rats in Group 3 (OA) were administered OA intravenously at a dose of 100 mg/kg BW. In Group 4 (pre-OA-α-LA), α-LA was given 15 minutes prior to OA infusion, and in Group 5 (post-OA-α-LA), α-LA was given two hours after OA infusion. Four hours after the OA infusion, rats were decapitated. Blood samples were collected to measure serum levels of malondialdehyde (MDA) and glutathione (GSH), and the levels of activity for superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). Lung tissue samples were taken for histopathological examination. Results: Exposure to OA resulted in increases in serum MDA levels (p<0.001), as well as histopathological lesions in lung tissue, and decreases in CAT (p<0.05), GSH-Px (p<0.05) activities and GSH (p<0.05) levels. On the other hand, MDA levels were decreased significantly (p<0.001), while CAT (p<0.05), GSH-Px (p<0.01) activities and GSH (p<0.05) levels were increased significantly in the pre-OA-α-LA group compared with the OA group. Conclusion: α-LA was found to lessen oxidative stress and to have positive effects on antioxidants in cases of OA-induced ALI. In conclusion, α-LA appears to have protective effects against ALI and potential for the prevention of ALI.

lipoic acid (LA) is a naturally occurring cofactor for mitochondrial enzymes, including pyruvate dehydrogenase (PDH) and-ketoglutarate dehydrogenase (KGDH). LA acts as a powerful micronutrient with diverse pharmacological properties. LA improves glucose uptake and insulin sensitivity, and thus decreases blood glucose levels and increases mitochondrial energy levels. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals from hydrogen peroxide and also scavenges reactive oxygen species, thereby increasing the levels of reduced glutathione. Via the same mechanisms, down-regulation of redox-sensitive inflammatory processes is achieved. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein. LA is currently studied for the treatment of some neurodegenerative diseases with diverse pathophysiology, including diabetic polyneuropathy and Alzheimer's disease (AD). For diabetic polyneuropathy, LA has been used for decades in Germany with a number of clinical trials showing benefits in insulin-stimulated glucose uptake and attenuating symptoms of neuropathy. In AD, an open-label trial in patients with mild and moderate AD is currently conducted at a at the memory clinic of the Henriettenstiftung hospital in Hannover, Germany. Interim analysis of the data after 4 years show that the progression rate of the patient treated with 600 mg LA daily is significantly slower than to the non-treated control group – particularly in early stages of dementia – and other control groups in published studies.

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.

Asian Journal of Pharmaceutical and Clinical Research, 2017

Objective: Antioxidant probably can prevent the progression and complications of Type 2 diabetes mellitus (T2DM). Due to effectiveness of alpha lipoic acid (ALA) as an antioxidant, this study was done in T2DM patients to evaluate the effect of ALA on their diabetic status, lipid profile, and oxidative stress (OS) status.Methods: A total of 35 patients with diabetes were selected randomly who were under insulin treatment mainly and grouped as Group “A.” Another age- and sex-matched healthy controls selected grouped as “B.” Both groups supplemented with ALA (300 mg/day) for 6 months continuously. All parameters were tested before and after the supplementation.Results: There was a significant decrease in fasting blood sugar from 161 to 122 mg/dl in Group “A” and from 98 to 90 mg/dl in Group “B.” Postprandial blood sugar (PPBS) and glycosylated hemoglobin (HbA1c) levels also significantly decreased from 211 to 158 mg/dl and 8.81% to 7.2%, respectively, in Group “A.” PPBS levels signif...

Archives of Biological Sciences, 2018

This review summarizes the effects of α-lipoic acid (LA) on liver damage and complications in diabetes and drug toxicity. LA is a naturally occurring dithiol compound that plays an essential role in mitochondrial metabolism in its protein-bound form. In contrast, free LA in supplements has diverse biological actions, and its antioxidant effect is its most studied and important activity. Due to its strong antioxidant potential, LA could have a promising role in the treatment of pathologies resulting from an imbalance in redox homeostasis. This includes diabetes, which produces deleterious effects on many organs, including the liver. In diabetes specifically, LA prevents β-cell destruction, enhances glucose uptake, and its antioxidant effects may be particularly useful in slowing down the development of diabetic complications. Diabetesrelated liver damage is a serious complication in which oxidative stress is the main contributor to tissue injury. Oxidative stress is regarded as one of the main pathological mechanisms underlying liver pathologies provoked by other insults, such as drug toxicity, where LA could also be a useful agent in therapeutic intervention. However, before wider application of LA in a clinical setting, experimental and clinical research needs to be extended..