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Alpha Lipoic Acid
Alpha Lipoic Acid - The Universal Antioxidant Alpha lipoic acid has been called the “universal” antioxidant. It boosts glutathione levels in cells, has potent antioxidant action in almost all the tissues of the body, and is a co-factor for some of the key enzymes (alpha keto acid dehydrogenases) involved in generating energy from food and oxygen in mitochondria. Alpha lipoic acid is known by a variety of technical names including thiotic acid, 1,2-dithiolane-3-pentanoic acid, 1,2-dithiolane-3-valeric acid, and 6,8-thiotic acid. When it functions as a co-factor for energy production, it is slightly modified and usually called lipomide or lipoate. When alpha lipoic acid was first isolated in the early 1950’s, it was tentatively classified as a vitamin because of its vitamin-like properties. The method by which alpha lipoic acid is synthesized within the body has not yet been fully characterized, but its precursors appear to be octanoate and the sulfur amino acid cysteine. Recent findings show that both alpha lipoic acid and its reduced form, dihydrolipoic acid (DHLA) function as potent antioxidants within the body, and that both these compounds may be effective in preventing and treating the complications of diabetes and, perhaps, aging itself. Alpha Lipoic Acid
Meets all Antioxidant Evaluation Criteria In his article,
Dr. Packer proposes that the following biochemical criteria be considered
when evaluating the antioxidant potential of a compound: Dr. Packer
then presents other important criteria for use when considering the preventive
and therapeutic applications of an antioxidant: After presenting these criteria, Dr. Packer makes it clear that an antioxidant need only meet a few of them to play an important role in the body. “A substance need not excel in meeting all these criteria to be considered a good antioxidant. For example, vitamin E acts only in the membrane or lipid domains, its dominant action is to quench lipid peroxyl radicals, and it has little or no activity against radicals in the aqueous phase, yet it is considered one of the central antioxidants of the body. Epidemiological studies are confirming its role in the prevention of numerous oxidant-related diseases, such as heart disease.” After reviewing
hundreds of studies dealing with the antioxidant properties of alpha lipoic
acid, Dr. Packer came to the following conclusions: Regeneration of
Other Antioxidants This ability of alpha lipoic acid to regenerate vitamin E was shown graphically in an experiment in which three groups of nude (hairless) 12-week-old mice were studied for six weeks. The first group of mice, (A), which received a normal diet during this period, developed normally. The second group of mice, (B), which were fed a vitamin E-deficient diet, showed marked signs of atrophy and degeneration. The third group of mice, (C), were fed a vitamin E-deficient diet supplemented with alpha lipoic acid. These animals showed none of the atrophy and degeneration found in the second group, indicating that the alpha lipoic acid had protected them against the degenerative effects of vitamin E deficiency. No Adverse Side
Effects
Caution: Supplement
Facts Suggested
Use:
LE Magazine March 1996 Alpha Lipoic
Acid Until recently, the antioxidants that fight damaging free radicals within the body were thought to be largely specialized in function. For example, the major function or the enzyme superoxide dismutase (SOD) is to inhibit superoxide radicals beta carotene's primary role is to quench singlet oxygen radicals; vitamin E's main role is to break lipid peroxide chains in cell membranes the primary function of glutathione is to knock out damaging hydroxyl radicals,and coenzyme Q10 (CoQ) fights off oxyradicals produced in the mitochondria (the power plants of the cells),which occurs in part as a result of CoQ's role in the generation of energy. Universal Antioxidants In recent years, however, Dr. Russell J. Reiter of the University of Texas at Austin and other scientists have produced evidence that the pineal hormone melatonin is a highly potent "universal" antioxidant found in virtually every cell of the body, and that it counteracts excessive free radical activity via several mechanisms in cell membranes as well as in the interior of cells. Melatonin plays an especially important role in fighting free radicals in the brain, where far more oxyradicals are generated than in any other part of the body because of the enormous amount of oxygen needed for brain metabolism. The discovery of the "universal" antioxidant power of melatonin is evidence of the existence of all purpose antioxidants that have across the board action against a wide spectrum of free radicals, and which, presumably, can substitute for the more specialized antioxidants when this becomes necessary. The "Universal" Action of Alpha Lipoic Acid There is now evidence of another "universal" antioxidant called alpha lipoic acid, which not only has potent,antioxidant action in virtually all the tissues of the body, but also is a co-factor for some of the key enzymes (alpha keto acid dehydrogeneses) involved to generating energy from food and oxygen in mitochondria. Alpha Lipoic Acid is known by a variety of names including thioctic acid, 1,2-dithiolane-3-pentanoic acid, 1,2-dithiolane-3 valeric acid, and 6,8-thioctic acid. Alpha lipoic acid functions as a co-factor for energy production as lipomide and is also called lipoate when functioning in this manner. When alpha lipoic acid was first isolated in the early 195Os, it was tentatively classified as a vitamin because of its vitamin like properties, but was later found (unlike vitamins) to be synthesized in both animals and humans. The method by which alpha lipoic acid is synthesized within the body has not yet been fully characterized but it appears as if two of its precursors are octanoate and the sulphur amino acid cysteine. Recent findings show that both alpha lipoic acid and its reduced form dihydrolipoic acid (DHLA) (Fig. 1) function as potent within the body and that both these compounds may be effective in preventing and treating the complications of diabetes and, perhaps, aging itself. Before we delve into the potential therapeutic benefits of alpha lipoic acid and DHLA, let's take a look at the findings showing their antioxidant properties.
In his article, Dr. Packer proposes that the following biochemical criteria be considered when evaluating the antioxidant potential of a compound:
- Specificity of free
radical quenching - Absorption and biovailability
After presenting these criteria, Dr. Packer makes it clear that an antioxidant need only meet a few of them to play an important role in the body. "A substance need not excel in meeting all the criteria to be considered a good antioxidant. For example, Vitamin E acts only in the membrane or lipid domains, its dominant action is to quench lipid peroxyl, and it has little or no activity against radicals in the aqueous phase, yet it is considered one of the central antioxidants of the body. Epidemiological studies are confirming its role in the prevention of numerous oxidant related diseases, such as heart disease". This is also true with regard to betacarotene, which has a specialized role (the quenching of singlet oxygen radicals) in the body, The long awaited findings of a long awaited findings of a long term study of the role of beta carotene in the prevention of age related diseases will show that subjects who took high levels of beta carotene every other day for 5 years had 50% fewer coronary or vascular events than subjects not taking beta carotene, and that the subjects taking beta carotene developed only a small fraction of the cancers developed in the control group. We'll be reporting the extraordinary details of these findings in Life Extension Magazine as soon as they are published. Dr. Packer's
Conclusions About After reviewing hundreds
of studies dealing with the antioxidant properties of alpha lipoic acid,
Dr. Packer came to the following conclusions: "An 'ideal' antioxidant would fulfill all of the above criteria. The alpha lipoic redox couple approaches the ideal; it has been called the 'universal antioxidant'. Alpha lipoic acid is readily absorbed from the diet. It is rapidly converted to DHLA in many tissues, as recent advances in assay technique have made evident. One or both of the components of the redox couple in both lipid and aqueous domains. Both DHLA and alpha lipoic acid have metal chelating activity. DHLA acts syngeristically with other antioxidants, including that it is capable of regenerating other antioxidants from their radical or inactive forms. Finally, there is evidence that they may have effects on regulatory proteins and on genes involved in normal growth and metabolism. One of the most beneficial effects of both alpha lipoic acid and DHLA is their ability to regenerate other essential antioxidants such as vitamin C, vitamin E, coenzyme Q10, and glutathione. The evidence is especially strong for the ability of DHLA to recycle vitamin E, which is apparently achieved directly by quenching tocopherol radicals or indirectly by reducing vitamin C or increasing the levels of ubiquinol (a derivative of CoQ) and glutathione, which, in turn, help to regenerate tissue levels oi vitamin E. The ability of alpha lipoic acid to regenerate vitamin E was shown graphically in an experiment in which three groups of nude (hairless) 12 week old mice were studied for six weeks. The first group of mice, (A), which received a normal diet during this period, developed normally. The second group of mice, (B), which were fed a vitamin E deficient diet showed marked signs of atrophy and degeneration. The third group of mice, (C), were fed a vitamin E deficient diet supplemented with alpha lipoic acid. These animals showed none of the atrophy and degeneration found in the second group, indicating that the alpha lipoic acid had protected them against the degenerative effects of vitamin E deficiency. (Fig. 2).
According to Dr. Packer: A schematic model has been put together (Fig. 3) showing the known biochemical pathways by which vitamin E is regenerated in cell membranes, so it can do battle again with the damaging lipid peroxide (peroxyl) radicals found in these membranes. Increasing Cellular Glutathione Levels Recent studies have shown that when alpha lipoic acid is added to various types of animal and human cells in tissue culture, it causes a 30-70% increase in cellular glutathione (GSH) levels. GSH levels have been found to increase dramatically in the lungs, liver, and kidney cells of mice injected daily with varying doses of alpha Iipoic acid for 11 days. GSH is an essential antioxidant, which scavenges hydroxyl radicals, the most dangerous type of free radicals found in the body. Analysis of these studies led Dr. Packer to conclude that: "It appears that alpha lipoic acid and DHLA act as antioxidants not only directly, through radical quenching and metal chelation, but indirectly as well, through recycling of other antioxidants and through the induction of increased intracellular levels of glutathione."
There is considerable evidence that alpha lipoic acid can be used to prevent and treat diabetes, both type I (juvenile diabetes) and type II (mature onset diabetes) and the complications of diabetes. Among the the most serious complications of diabetes is nerve damage, especially in the eye (retinopathy) and heart attacks resulting from atherosclerosis. The two most popular mechanisms of action proposed as the causes of these consequences of diabetes are excessive free radical damage and glycosylation (or glycation), which involves glucose (blood sugar) induced modifications in proteins leading to molecular cross linking of these proteins in the lens of the eye, cell membranes, and in connective tissues such as collagen and elastin. Glucose induced cross linking of proteins has been proposed as a primary cause of the increasing rigidity and narrowing of arteries with advancing age that contributes to the onset of heart attacks and strokes, as well as the aggregation of malfunctioning neurons that causes nerve damage and contributes to the neuritic plaques and neurofibrillary tangles characteristic of Alzheimer's disease and other neurodegenerative diseases. The glycation process has also been proposed as a basic cause of aging in nerve cells, muscle cells, and the connective tissues that hold us together. Prevention And Treatment Of Diabetes There is solid evidence in both animals and humans that alpha lipoic acid can help to prevent and treat the pathologies of diabetes through its antioxidant and antiglycation effects. Type I (insulin dependent) diabetes results from destruction of the beta cells of the pancreas by immunlogic or inflammatory attack. One animal model for this type of diabetes is the non obese diabetic mouse, which has been specially bred to get diabetes. When the development of diabetes was accelerated in these mice by the administration of the drug cyclophosphamide, 60% of the mice developed full-fledged diabetes in 1-3 weeks, but if these mice were injected with alpha lipoic acid (10mg/kg) for 10 days before and 10 days after cyclophosphamide administration, only 30% of the mice developed diabetes. Effects On Glucose Uptake In Type II Diabetes The primary characteristic of type II diabetes is insulin resistance. Most type II diabetics produce plenty of insulin, but are unable to make effective use of the insulin they produce. As a result, improvement in the utilization of insulin in skeletal muscle has been the basis of many studies seeking to find an effective therapy to reverse insulin resistance. Since skeletal muscle is the major repository for glucose following a meal, agents that enhance glucose utilization in skeletal muscle (through the action of insulin) are potentially useful in the long term treatment of type II diabetes. In animal studies, alpha lipoic acid has been shown to improve glucose utilization in skeletal muscle, isolated rat diaphragm, heart muscle, and other types of tissue. Using the obese Zucker rat as an animal model of obese rats prone to type II diabetes, Henrikson and colleagues demonstrated that alpha lipoic acid treatment markedly increased utilization of glucose in the absence or presence of insulin. Acute treatment with a single dose of 100 mg/ kg of alpha lipoic acid for one hour or chronic treatment (30 mg/kg for 10 days) produced a 50% improvement in glucose uptake in the skeletal muscles of the experimental animals. Human Studies In Type II Diabetics In a study of 13 type II diabetes, Jacob and associates from the Institute Of Medicine in Baden-Baden, Germany found that intravenous injections of 1,000 mg of alpha lipoic acid enhanced insulin stimulated whole body disposal of glucose by about 50%. This was the first clinical study to show that alpha lipoic acid has a profound beneficial effect on the utilization of glucose by type II diabetics. In another human study in Germany, patients with long term type II diabetes were divided into four groups and given either 600 mg. of alpha lipoic acid, 100 micrograms of selenium (sodium selenite), 1,200 IU of vitamin E (alpha tocopherol), or placebo every day for 3 months. All three of the experimental groups showed evidence, in contrast to the control group, of reduced free radical activity, as measured by serum concentrations of thiobarbituric acid and excretion of albumin (two measures of free radical activity), and "highly significant" improvement in the incidence and severity of diabetic neuropathies. The scientists concluded that: "These results prove that oxidative stress plays a role in promoting the development of long term diabetic late complications and that antioxidant therapy leads to a regression of diabetic late complications in type II diabetics." Alpha Lipoic Acid One of the most damaging complications of diabetes is nerve damage at various sites of the body, which inactivates and weakens muscles, can be extremely painful, and can cause blindness when the retina of the eye is attacked (diabetic retinopathy). Alpha lipoic acid has been shown to be highly effective in treating such neuropathies. The clinical benefits of alpha lipoic acid in diabetics was discovered by Beck and Schneeweiss in 1959. There have been a half dozen or so studies since then confirming these results. In a placebo controlled, double blind study, 20 diabetics were given intravenous infusions of 200 mg a day of alpha lipoic acid or placebo for 21 days. The results showed dramatic improvement in some clinical symptoms in some of the experimental subjects. For example, before being treated with alpha lipoic acid, four patients had severe pain and six patients had moderate pain. After treatment, five of the patients had no pain, four had moderate pain, and only one had severe pain. In a longer single
blind study, alpha lipoic acid was compared to vitamin B1 as a treatment
for diabetic neuropathy. In this study, 600 mg/day of alpha lipoic acid
or 400 mg mg/day of vitamin B1 were administered intravenously and intramuscularly,
respectively, to diabetics for 3 weeks, followed by 12 weeks of oral administration
of the same doses. Pain and parethesia were reduced significantly in the
alpha lipoic acid patients compared to the vitamin B1 patients. Fig. 4 is a schematic diagram showing the various mechanisms by which alpha lipoic acid supplementation benefits diabetes patients. Alpha Lipoic Acid Protects Against Nerve Cell Death In recent years, scientists have found found a method of nerve cell death in stroke and neurodegenerative disorders such as Parkinson's disease and Huntington's disease is excitotoxicity (excessive activation) of NMDA (N-methyl-D-aspartate receptors, and the subsequent generation of nitric oxide, free radical induced lipid peroxidation, aberrantly increased calcium concentration, and mitochondrial dysfunction leading to, depleted energy supplies. There is evidence that depletion of reduced glutathione makes neurons more susceptible to excitotoxicity, and that intact mitochondrial function is essential for neuronal resistance to to excitotoxic attack. It is believed, for example, that reduced levels of the energy currency of the cell (ATP) that accompanies loss of mitochondrial function causes depolarization of neuronal membrane, which exposes NMDA receptors to excessive levels of glutamate. The resulting neurohormonal cascade leads, in many cases, to the death of neurons in the brain, and central and peripheral nervous systems. Scientists have been trying to develop, antyi-excitotoxic therapies that are NMDA receptor antagonists this counter this kind of neuronal cell death. A recent study at the Dept. Of Neurology at the University of Rochester, N.Y.at the University of Rochester Medical Center in Rochester, N.Y. demonstrated that alpha lipoic acid protected against glutamate and malonic acid induced lesions in the brains of male Sprague-Dawley rats. They found a significant reduction of Iesions in animals receiving 10 mg/kg injections of either alpha lipoic: acid or DHLA (Fig. 5). The University of Rochester scientists concluded that: "Excessive activation of NMDA receptors by glutamate has been implicated in the neuronal damage associated with hypoxia/ischemia and hypoglycemia. In contrast, it is hypothesized that chronic neurodegenerative disorders may involve a form of secondary excitotoxicity induced by metabolic or membrane defects rather than excessive glumate release. The fact that thiotic acid (alpha lipoic acid) and dihydrolipoic acid (DHLA) are neuroprotective against both direct and secondary excitotocity suggest a possible role for these endogenous compounds in the treatment of acute and chronic neurological disorders. In this regard, it is worth nothing that thiotic acid is an approved drug for the treatment of diabetic polyneuropathy in Germany" Further evidence that
alpha lipoic acid can provide therapeutic benefits in patients with neuropathies
comes from tissue culture studies in which exposure to alpha lipoic acid
resulted in the sprouting of neurites (the small branches at the end of
neurons) in early stage rat neurons that far exceeded that round in control
neurons. In this study, which was conducted at the Max Planck Institute For Physiology in Frankfort, Germany, the length of the neurites in the alpha lipoic acid treated neurons was five times that of the untreated neurons and there were far more branchings in the experimental tissue culture neurons. These changes were dose dependent. The more alpha lipoic acid added to the culture medium the greater the density and length of the neurons. The scientists concluded that, since the first step in neuronal regeneration consists of neuronal regeneration consists of neurite elongation, this finding suggests that alpha lipoic acid may be able to help regenerate neurons in humans, which would make it a potentially useful therapy for brain diseases such as Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, and other age-related neurodegenerative diseases. Improved Memory In Aged Mice To test the hypothesis treatment with the appropriate free radical scavenger can improve age-related memory deficit, researchers at the Clinical Institute for Mental Health in Mannheim , Germany used aged female NMRI mice, who have demonstrated to exhibit specific well defined memory deficits with advancing age, as well as deficits of NMDA receptors density, which have been linked to age-related cognitive decline.
The German scientists gave old. but healthy 20-23 month old female alpha lipoic acid at 100 mg/kg of body weight dissolved in Methocel (1%) administered orally once a day for 15 days, with controls receiving Methocel alone. The treatment was started 14 days before the beginning of behavioral memory testing. A second group of aged mice used for biochemical analysis was also treated for 15 days, and a third group of young (3-4 months) mice were tested as well. The mice were tested on their ability to explore a series of maze like compartments within a special area. The results showed that two factors influenced learning and memory age and treatment with alpha lipoic acid. The scientists found that long term memory, but not short term memory or learning was impaired in aged female NMRI mice with the repetition of trials. On the other hand, the mice treated with alpha lipoic acid showed marked improvement in learning and memory when compared to aged, untreated controls. This improvement of cognitive function was correlated with an increase in NMDA receptor density, suggesting that the memory enhancing effects of alpha lipoic acid may be linked to the age related decline in the density of these receptors. Effects On Cataract Formation Another common complication of diabetes is cataract formation in the eye, which can lead to blindness. In animal studies supplementation with alpha lipoic acid has prevented cataract formation caused by inhibition of glutathione synthesis. These studies showed that alpha lipoic acid reduced cataract formation by 40% by protecting the lens of the eye from the loss of vitamin C, vitamin E, and glutathione, which occurred in unsupplemented control animals.
Protection Against Atherosclerosis Diabetics have a significantly higher incidence of atherosclerosis than healthy people. There is substantial evidence that the ability of alpha lipoic acid to counteract glucose modification of proteins (glycation) plays an important role in protecting us against atherosclerosis. Both alpha lipoic acid and DHLA have been shown to protect a wide variety of tissues from the protein cross links produced by glycation, and the oxidation of LDL cholesterol, which plays a critical role in the formation of atherosclerotic plaques. This process is a cause of high blood pressure, heart attacks and strokes. Much has been written about the ability of aminoguanidine and chromium to counteract the molecular cross links caused by glycation, but it appears as if alpha lipoic acid may be even more effective than both these compounds in countering the degenerative effects of glycation. This suggests that alpha lipoic acid may play a role in preventing some of the aspects of normal aging, as well as in protecting us against diabetes and neurodegenerative diseases. Protection Against Other Pathologies Among the other therapeutic uses for alpha lipoic acid has been the treatment of liver disease caused by excessive alcohol intake, as an antidote for various types of Coed poisoning, as a means of countering the effects of ischemic (reduced blood flow) and reperfusion injury, as a means of protecting against heavy metal poisoning, radiation in- jury, and the effects of cigarette smoking. No Adverse Side Effects In all the clinical studies to date with alpha lipoic acid, there have been no reported serious adverse side effects, even at the high doses used to treat diabetics and patients suffering from neurodegenerative diseases. Among the mild, reversible side effects found in some patients have been allergic skin reactions, and possible hypoglycemia in diabetics.
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The
Universal Antioxidant
