DESCRIPTION
Alpha-lipoic acid, also known as thioctic acid, is a disulfide compound that is a cofactor in vital energy-producing reactions in the body. It is also a potent biological antioxidant. Alpha-lipoic acid was once thought to be a vitamin for animals and humans. It is made endogenously in humans—the details of its synthesis are still not fully understood—and so it is not an essential nutrient. There are, however, certain situations, for example, diabetic polyneuropathy, where alpha-lipoic acid might have conditional essentiality. And recent research indicates that the antioxidant roles of alpha-lipoic acid may confer several health benefits. Alpha-lipoic acid is found widely in plant and animal sources.
Most of the metabolic reactions in which alpha-lipoic acid participates occur in mitochondria. These include the oxidation of pyruvic acid (as pyruvate) by the pyruvate dehydrogenase enzyme complex and the oxidation of alpha-ketoglutarate by the alpha-ketoglutarate dehydrogenase enzyme complex. It is also a cofactor for the oxidation of branched-chain amino acids (leucine, isoleucine and valine) via the branched-chain alpha-keto acid dehydrogenase enzyme complex.
Alpha-lipoic acid is approved in Germany as a drug for the treatment of polyneuropathies, such as diabetic and alcoholic polyneuropathies, and liver disease.
Alpha-lipoic acid contains a chiral center and consists of two entantiomers, the natural R- or D- entantiomer and the S- or L- entantiomer. Commercial preparations of alpha-lipoic acid consist of the racemic mixture, i.e. a 50/50 mixture of the R- and E-entantiomers. It is represented by the following chemical structure:
Alpha-Lipoic acid
Alpha-lipoic acid has a variety of names. In addition to being known as alpha-lipoic acid and thioctic acid, it is also known as lipoic acid, 1,2-dithiolane-3-pentanoic acid; 1,2-ditholane-3-valeric acid; 6,8-thiotic acid; 5-[3-C1,2-dithiolanyl)]-pentanoic acid; delta-[3-(1,2-dithiacyclopentyl)] pentanoic acid; acetate replacing factor and pyruvate oxidation factor. Alpha-lipoic acid is water-insoluble.
Although the details of its synthesis have yet to be worked out, alpha-lipoic acid is synthesized in mitochondria; octanoic acid and L-cysteine (for its sulfur) are precursors in its synthesis.
ACTIONS AND PHARMACOLOGY
ACTIONS
Alpha-lipoic acid has biological antioxidant activity, antioxidant recycling activity and activity in enhancing biological energy production.
MECHANISM OF ACTION
Alpha-lipoic acid and its reduced metabolite, dihydrolipoic acid (DHLA), form a redox couple and may scavenge a wide range of reactive oxygen species. Both alpha-lipoic acid and DHLA can scavenge hydroxyl radicals, the nitric oxide radical, peroxynitrite, hydrogen peroxide and hypochlorite. Alpha-lipoic acid, but not DHLA, may scavenge singlet oxygen, and DHLA, but not alpha-lipoic acid, may scavenge superoxide and peroxyl reactive oxygen species.
Alpha-lipoic acid has been found to decrease urinary isoprostanes, O-LDL and plasma protein carbonyls, markers of oxidative stress. Further, alpha-lipoic acid and its redox couple DHLA have been found to have antioxidant activity in aqueous, as well as in lipophilic regions, and in extracellular and intracellular environments. Finally, with regard to alpha-lipoic acid's antioxidant activity, alpha-lipoic acid appears to participate in the recycling of other important biologic antioxidants, such as vitamins E and C, ubiquinone and glutathione.
Exogenous alpha-lipoic acid has been shown to increase ATP production and aortic blood flow during reoxygenation after hypoxia in a working heart model. It is thought that this is due to its role in the oxidation of pyruvate and alpha-ketoglutarate in the mitochondria, ultimately enhancing energy production. This activity, and possibly its antioxidant activity, may account for its possible benefit in diabetic polyneuropathy.
PHARMACOKINETICS
Most pharmacokinetic studies have been performed in animals. Alpha-lipoic acid is absorbed from the small intestine and distributed to the liver via the portal circulation and to various tissues in the body via the systemic circulation. The natural R-entantiomer is more readily absorbed than the L-entantiomer and is the more active form. Alpha-lipoic acid readily crosses the blood-brain barrier. It is found, after its distribution to the various body tissues, intracellularly, intramitochondrialy and extracellularly.
Alpha-lipoic acid is metabolized to its reduced form, dihydrolipoic acid (DHLA), by mitochondrial lipoamide dehydrogenase. DHLA, together with lipoic acid, form a redox couple. It is also metabolized to lipoamide, which functions as the lipoic acid cofactor in the multienzyme complexes that catalyze the oxidative decarboxylations of pyruvate and alpha-ketoglutarate. Alpha-lipoic acid may be metabolized to dithiol octanoic acid, which can undergo catabolism.
INDICATIONS AND USAGE
Lipoic acid shows evidence of being effective in the treatment of diabetic neuropathy and may be useful in treating some other aspects of diabetes. It may help prevent the oxidation of LDL cholesterol and may be protective, generally, against oxidative stress and, specifically, against atherosclerosis, ischemia-reperfusion injury and various radiologic and chemical toxins. It may also be useful in some inborn metabolic disorders. There is less evidence that it might be helpful in some neurodegenerative conditions. There is preliminary evidence that it might have some immune-modulating effects. It has been suggested that lipoic acid may slow aging of the brain and that it may be an anti-aging substance, in general.
RESEARCH SUMMARY
Lipoic acid is an approved treatment for diabetic neuropathy in Germany. Numerous studies in both animals and humans have produced promising results with lipoic acid in this neuropathy. In animal models and culture studies, lipoic acid has demonstrated antioxidant properties that help reduce or eliminate a sequence of events that include reduced endoneural blood flow and oxygen tension, which are pre-requisites of neuropathy. In addition, some of these studies have revealed favorable lipoic acid effects that appear to be independent of its antioxidant properties, including increased glucose uptake, promotion of new neurite growth and chelation of transition metals thought to play a role in diabetic neuropathy.
In some animal experiments, lipoic acid, administered for up to three months, significantly reversed the increase in nerve vascular resistance and the decrease in nerve blood flow in diabetic rats. Nerve conduction velocity was entirely restored in some nerve groups after three months of treatment.
Human clinical trials have been similarly encouraging. In one of these studies, subjects received 200 milligrams of intravenous lipoic acid daily. After 21 days, significant pain reduction was achieved in most subjects.
In a larger, multi-center, double-blind, randomized, placebo-controlled study of 328 patients with type 2 diabetes, significant improvements were recorded in several clinical measures of diabetic polyneuropathy, including pain, numbness, paresthesia and burning sensations. These results were evident after three weeks of intravenous lipoic acid given five times weekly in doses of 600 and 1200 milligrams.
Nerve conduction velocity has not been shown to improve in the short-term human studies conducted so far. One group of researchers has suggested that proof of neurophysiological improvement in these neuropathies may emerge from long-term lipoic acid supplementation studies, as has been the case in some animal model studies. "A period of several years," they have observed, "is required to slow progress of diabetic neuropathy due to normalization of blood glucose levels."
There is evidence, too, that lipoic acid may help prevent or slow the development of the atherosclerosis for which diabetics are at higher risk. It may do this, in part, through a gene-regulatory mechanism that helps prevent endothelial cell activity that has been implicated in the progression of atherosclerosis.
With respect to atherosclerosis, in general, lipoic acid's antioxidant and metabolic effects appear to offer some protection, as demonstrated in various animal models. Recently, researchers demonstrated, in a 16-week randomized trial, that lipoic acid, in oral doses of 600 milligrams daily for eight weeks, significantly inhibits the oxidation of LDL-cholesterol in healthy human subjects. The supplements also significantly reduced levels of F-2 isoprostanes, markers of oxidative stress. In this study, lipoic acid proved to be superior to vitamin E in decreasing levels of plasma protein carbonyls. Protein oxidation and LDL-cholesterol oxidation are implicated in heart disease.
Various animal studies have suggested that lipoic acid can prevent or reduce cell and tissue damage in heart attacks and stroke. There is extensive animal work showing that lipoic acid can exert significant protective effects against ischemia-reperfusion injury.
Lipoic acid is believed to work in this context, at least in part, through its antioxidant properties and its reported ability to increase cellular levels of glutathione that are typically depleted by the reactive oxygen species formation that characterizes ischemia-reperfusion. More research is needed to further elucidate these mechanisms and determine whether these results will apply in humans.
Animal work is also suggestive of some modest benefit from lipoic acid in the treatment of various neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and Huntington's disease. Results to date, however, remain inconclusive. Clinical studies are needed.
There is some evidence that children afflicted with inborn errors of pyrurate metabolism may derive some benefit from lipoic acid treatment. Those with Wilson's disease, a genetic disorder characterized by disturbed copper metabolism, may be helped by lipoic acid as well. The supplement has also proved useful in conferring some protection against cadmium poisoning and hexane inhalation. It has also been used in some liver toxicities, such as Amanita phalloides mushroom poisoning.
Lipoic acid's role in immunity is not well understood. There are reports that it can augment antibody response in some animal models of immunosuppression. This research warrants followup.
Claims that lipoic acid slows aging of the brain and is an anti-aging substance generally seem to be related to its potent antioxidant properties. Direct proof of anti-aging is lacking, but there is some animal work suggestive of some possible anti-aging effects.
Rats were fed a lipoic-acid supplemented diet to see whether the substance can reverse age-related declines in metabolism and mitochondrial function. Unsupplemented aged rats (24 to 26 months) exhibited ambulatory activity, said to be a general measure of metabolic activity, that was threefold lower than that of young controls. But this decline was significantly reversed in similarly aged rats supplemented with lipoic acid for two weeks.
Hepatocytes from untreated aged rats, compared with hepatocytes of young controls (three to five months), had significantly lower oxygen consumption and mitochondrial membrane potential. But in supplemented aged rats, hepatocytes, by the same measures, were comparable to those of the young controls.
Lipoic acid supplementation was reported to completely reverse age-related declines in hepatocyte ascorbic acid and glutathione levels. There was additional evidence of decreased oxidative damage in the lipoic-acid supplemented aged rats. The researchers concluded: "Little is known about whether lipoic acid may be an effective anti-aging supplement...in humans. Our present findings using rats would suggest that lipoic acid supplementation may be a safe and effective means to improve general metabolic activity and increase antioxidant status, affording increased protection against external oxidative and xenobiotic insults with age." Again, further study is needed.
CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS
CONTRAINDICATIONS
None known.
PRECAUTIONS
Because of lack of long-term safety data, alpha-lipoic acid should be avoided by pregnant women and nursing mothers.
Those with diabetes and problems with glucose intolerance are cautioned that supplemental alpha-lipoic acid may lower blood glucose levels. Blood glucose should be monitored and antidiabetic drug dose adjusted, if necessary, to avoid possible hypoglycemia.
ADVERSE REACTIONS
To date, alpha-lipoic acid in doses up to 600 milligrams daily has been well tolerated. There is evidence in typeII diabetes that 1800mg per day had very beneficial effects in reducing blood sugar and weight, together with producing an abundance of energy. The dose is weight and diet related.
INTERACTIONS
Supplemental alpha-lipoic acid may lower blood glucose levels. Those with diabetes on antidiabetic medication should have their blood glucose monitored and antidiabetic drug dose appropriately adjusted, if necessary, to avoid possible hypoglycemia.
OVERDOSAGE
There are no reports of alpha-lipoic acid overdosage.
DOSAGE AND ADMINISTRATION
Alpha-lipoic acid is available as a racemic mixture of D- and L- entantiomers. Some studies showing significant antioxidant effects have used doses of the racemic mixture (r,s-alpha lipoic acid) of 600 milligrams daily.
Alpha-lipoic acid is available in Germany as a drug to treat polyneuropathy, such as diabetic polyneuropathy, and liver disorders. It is available for oral and parenteral use. Those with diabetic neuropathy use 300 milligrams daily of the oral preparation, taken in divided doses.
Coenzyme Q10 (CoQ10)
DESCRIPTION
Coenzyme Q10 or CoQ10 belongs to a family of substances called ubiquinones. Ubiquinones, also known as coenzymes Q and mitoquinones, are lipophilic, water-insoluble substances involved in electron transport and energy production in mitochondria. The basic structure of ubiquinones consists of a benzoquinone "head" and a terpinoid "tail." The "head" structure participates in the redox activity of the electron transport chain. The major difference among the various coenzymes Q is in the number of isoprenoid units (5-carbon structures) in the "tail." Coenzymes Q contain one to 12 isoprenoid units in the "tail"; 10 isoprenoid units are common in animals.
Coenzymes Q occur in the majority of aerobic organisms, from bacteria to plants and animals. Two numbering systems exist for designation of the number of isoprenoid units in the terpinoid "tail": coenzyme Qn and coenzyme Q(x). N refers to the number of isoprenoid side chains, and x refers to the number of carbons in the terpinoid "tail" and can be any multiple of five. Thus, coenzyme Q10 refers to a coenzyme Q having 10 isoprenoid units in the "tail." Since each isoprenoid unit has five carbons, coenzyme Q10 can also be designated coenzyme Q(50). The structures of coenzymes Q are analogous to those of vitamin K2.
Coenzyme Q10 is also known as Coenzyme Q(5O), CoQ10, CoQ(50), ubiquinone (50), ubiquinol— 10 and ubidecarerone. Chemically, CoQ10 is known as 2, 3-dimethyoxy-5-methyl-6-decaprenyl-1,4-benzoquinone, and its structural formula is:
CoEnzyme Q10
It is a solid wax-like substance. CoQ10 is the predominant form in humans, and CoQ9 is the predominant form in rats.
Supplemental CoQ10 is typically derived from tobacco leaf extracts and fermented sugar cane and beets.
ACTIONS AND PHARMACOLOGY
ACTIONS
Supplemental CoQ10 may have cardioprotective, cytoprotective and neuroprotective activities.
MECHANISM OF ACTION
Since the actions of supplemental CoQ10 have yet to be clarified, the mechanism of these actions is a matter of speculation. However, much is known about the biochemistry of CoQ10. CoQ10 is an essential cofactor in the mitochondrial electron transport chain, where it accepts electrons from complex I and II, an activity that is vital for the production of ATP.
CoQ10 has antioxidant activity in mitochondria and cellular membranes, protecting against peroxidation of lipid membranes. It also inhibits the oxidation of LDL-cholesterol. LDL-cholesterol oxidation is believed to play a significant role in the pathogenesis of atherosclerosis.
CoQ10 is biosynthesized in the body and shares a common synthetic pathway with cholesterol. CoQ10 levels decrease with aging in humans. Why this occurs is not known but may be due to decreased synthesis and/or increased lipid peroxidation which occurs with aging.
PHARMACOKINETICS
CoQ10 is absorbed from the small intestine into the lymphatics; from there it enters the blood. Absorption of CoQ10 is poor. Well over 60% of an oral dose is excreted in the feces. Furthermore, absorption of CoQ10 is highly variable and depends not only on food intake but also on the amount of lipids present in the food. Absorption is lower on an empty stomach and greater when taken with food of high lipid content. In the blood, CoQ10 is partitioned into the various lipoprotein particles, including VLDL, LDL and HDL.
It takes about three weeks of daily dosing with CoQ10 to reach maximal serum concentrations, which then plateau with continuous daily dosing. CoQ10 is distributed to the various tissues of the body and is able to enter the brain. The main elimination of CoQ10 occurs via bile.
INDICATIONS AND USAGE
Coenzyme Q10 may be indicated in cardiovascular disease, particularly in congestive heart failure. It may also be indicated to correct reduced blood levels of CoQ10 that result from the use of HMG-CoA reductase inhibitors used to treat elevated cholesterol levels. It also appears to have usefulness in the management of periodontal disease in some.
RESEARCH SUMMARY
There are many studies, spanning more than two decades, reporting positive results from the use of CoQ10 as adjunctive therapy in the treatment of congestive heart failure. CoQ10 has been an approved drug in Japan for use in congestive heart failure since 1974. It has also been approved for this use in some other countries. Several studies have demonstrated a strong correlation between severity of heart disease and severity of CoQ10 deficiency. Some have suggested that this deficiency is the primary cause of some variations of heart muscle dysfunction, while others believe it plays a secondary role in the etiology of heart failure.
Early studies of congestive heart failure focused on idiopathic dilated cardiomyopathy, testing CoQ10 against placebo using echocardiography to assess heart function. Echocardiographic improvement seen in these studies was generally slow but sustained and was accompanied by diminished fatigue, chest pain, dyspnea and palpitations. Normal heart size and function were restored in some patients using only CoQ10; this occurred primarily in patients with recent onset of congestive heart failure.
Subsequently, nearly all of the several placebo-controlled studies investigating CoQ10's effects on heart muscle function have reported significant positive results. One multi-center Italian study included 2,664 patients with congestive heart failure. No notable adverse effects on drug interactions have been reported in these studies except for one report that noted a slight diminution in coumadin (warfarin) activity.
Many studies to date have examined CoQ10 as an addition to standard medical treatments. In several studies involving hypertension and other manifestations of cardiovascular disease, there was a significant reduction in the use of concomitant drug therapies when CoQ10 was added to the treatment regimen.
It is now known that the HMG-CoA reductase inhibitors (statins, eg lipitor etc), while very effective in lowering cholesterol levels, also significantly lower levels of CoQ10. This may be particularly hazardous for patients with heart failure, suggesting a possible indication for CoQ10 in many, if not all, individuals using these cholesterol-lowering drugs. There has been some suggestion that CoQ10, especially if it could be more readily absorbed, might be a cholesterol-lowering agent itself. There is, however, no evidence for this.
Significant CoQ10 deficiencies have been noted in diseased gingiva. CoQ10's efficacy in reducing gingival inflammation and periodontal pocket-depth has been demonstrated in placebo-controlled trials. Claims that CoQ10 might be an effective anti-cancer agent are based upon a few suggestive case histories that will require far more rigorous clinical investigation before these claims can be properly evaluated. Similarly, claims that CoQ10 might be useful in AIDS and some other immune dysfunctions are premature.
It is not unreasonable to hypothesize that CoQ10 might be helpful in muscular dystrophy—and there is some very preliminary animal and clinical data suggesting that it might be. Muscular dystrophy is usually associated with cardiac disease. Research is ongoing but, to date, is inconclusive.
There is also some evidence that CoQ10 might boost energy and speed recovery of exercise-related muscle exhaustion and damage. This work, too, needs more rigorous followup.
There is no evidence that CoQ10 can inhibit obesity.
CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS
CONTRAINDICATIONS
None known.
WARNINGS AND PRECAUTIONS
There is one report of CoQ10 decreasing the effectiveness of warfarin. Those taking warfarin should be aware of this possibility.
Because of lack of long-term safety studies, pregnant women and nursing mothers should avoid CoQ10 supplements.
Clinical reports from Japan suggest that supplemental CoQ10 may improve beta-cell function and glycemic control in type II diabetics. CoQ10 does not appear to improve glycemic control in type I diabetics. Diabetics should be made aware of this possibility, and those diabetics who do use supplemental CoQ10 should determine by appropriate monitoring if they need to make any adjustments in their diabetic medications. (see lipoic acid)
ADVERSE REACTIONS
Mild gastrointestinal symptoms such as nausea, diarrhea and epigastric distress have been reported, particularly with higher doses (200 milligrams or more daily). The side effect is temporary and in much larger doses, up to 1500mg per day one report of vision acuity lasting for one day was reported.
INTERACTIONS
DRUGS
Warfarin: There is one report of CoQ10 decreasing the effectiveness of warfarin.
Statins: CoQ10 and cholesterol share the same metabolic pathways. Inhibition of the enzyme 3-hydroxyl-3-methylglutonyl coenzyme A (HMG-CoA) reductase would be expected to decrease CoQ10 levels. The statin drugs lovastatin, simvastatin and pravastatin are known to decrease CoQ10 levels in humans. It is likely that all statins have this effect.
Doxorubicin: CoQ10 may help ameliorate the cardiotoxicity of doxorubicin.
Antidiabetic medications: CoQ10 may improve glycemic control in some type II diabetics. If this were to occur, antidiabetic medications might need appropriate adjusting.
Beta Blockers: Some beta blockers, in particular propanolol, have been reported to inhibit some CoQ10-dependent enzymes
Piperine: Piperine, found in black pepper, may increase plasma levels of CoQ10. However it is mitochondrial levels that are important as CoQ10 remaining in blood is excreted.
DOSAGE AND ADMINISTRATION
CoQ10 is available in different formulations: oil-based capsules, powder-filled capsules, and tablets and solubilized softgels (microemulsions and others).
Daily doses of CoQ10 range from 5 to 300 milligrams. Those who use CoQ10 for periodontal health take 100 to 150 milligrams daily. Effectiveness, if any, is thought to be obtained with doses of 50 to 200 milligrams daily. The same dose range applies to those who take statin drugs for treatment of hypercholesterolemia.
CoQ10 is best taken with food. About three weeks of daily dosing are necessary to reach maximal serum concentrations of CoQ10.
CoQ10 is also available topically in some toothpastes and skin creams.
History
In 1999 we looked at a relatively new antioxidant supplement called alpha-lipoic acid (ALA) and concluded that it might one day prove to be very important, but that it was too early to recommend it. Since then more studies on it have been done. Is the evidence today strong enough to support its use? Scientists first discovered the importance of ALA in the 1950s, and recognized it as an antioxidant in 1988.
It has been the subject of a tremendous amount of basic research around the world, some being done at the University of California, Berkeley by Dr. Lester Packer, a leading expert on antioxidants. The body needs ALA to produce energy. It plays a crucial role in the mitochondria, the energy-producing structures in cells. The body actually makes enough ALA for these basic metabolic functions. This compound acts as an antioxidant, however, only when there is an excess of it and it is in the “free” state in the cells. But there is little free ALA circulating in your body, unless you consume supplements or get it injected. Foods contain only tiny amounts of it. What makes ALA special as an antioxidant is its versatility—it helps deactivate an unusually wide array of cell damaging free radicals in many bodily systems.
In particular, ALA helps protect the mitochondria and the genetic material, DNA. As we age, mitochondrial function is impaired, and it’s theorized that this may be an important contributor to some of the adverse effects of aging. ALA also works closely with vitamin C and E and some other antioxidants, “recycling” them and thus making them much more effective.
ALA is being studied in animals and in humans as a preventive and/or treatment for many age-related diseases. These range from heart disease and stroke to diabetes and Parkinson’s and Alzheimer’s disease, as well as declines in energy, muscle strength,
brain function, and immunity. It is also being studied for HIV disease and multiple sclerosis. In Germany, in particular, it is already prescribed to treat long-term complications of diabetes, such as nerve damage, thought to result in part from free-radical damage; there is also evidence that it can help decrease insulin resistance and thus help control blood sugar. Many studies have yielded promising results; others are still underway.
Diseases
Multiple sclerosis (MS) is an immune mediated disease of the central nervous system that affects over 350,000 Americans. T lymphocytes, macrophages and soluble mediators of inflammation cause demyelination and axonal injury in MS. Chronic relapsing experimental autoimmune encephalomyelitis (EAE) in SJL mice models MS clinically and pathologically and is useful for testing potential therapies for MS. Activated macrophages release nitric oxide and oxygen free radicals that cause demyelination and axonal injury in MS and EAE. Natural anti-oxidants potentially could favorably influence the course of MS by decreasing oxidative injury. This project will assess three natural anti-oxidant regimens, ginkgo biloba, alpha-lipoic acid/essential fatty acids and vitamin E/selenium, for their potential as treatments for MS. For Aim 1, we will test each of the three anti-oxidant regimens for their ability to suppress EAE. For Aim 2, we will evaluate the anti-oxidant regimens that suppress EAE for their ability to decrease markers of lipid, protein and DNA oxidative injury in blood and cerebrospinal fluid in patients with MS.
Based on the results from Aims 1 and 2, we will select the anti-oxidant regimen that appears most effective at suppressing EAE and decreasing markers of oxidative injury in patients with MS. For Aim 3, we will perform a Phase I/II trial in patients with MS to determine if the selected anti-oxidant regimen can decrease disease activity as detected with gadolinium enhanced magnetic resonance imaging. The results of this study will serve as the basis for a Phase III trial to assess the long term effectiveness of natural anti-oxidant therapy in MS.
Atherosclerosis
Atherosclerosis and its associated vascular complications are the principal cause of cardiovascular and cerebrovascular diseases (CVDs) leading to myocardial infarction (heart attacks) and stroke (“brain attacks”), respectively. CVDs are the principal cause of death in Western civilizations, accounting for more than 40% of all deaths. According to the American Heart Association’s 2003 Heart and Stroke Statistical Update, almost 62 million Americans suffer from CVDs, which have been the number one killer in the U.S. for more than nine decades.
Epidemiological studies over the past 50 years have revealed numerous risk factors for atherosclerosis, which can be grouped into factors with an important genetic component and those that are largely environmental. These environmental factors are of great importance for the general population. About 70% of strokes and 80% of heart attacks are potentially preventable by diet and lifestyle modifications, including nonsmoking, a healthy diet (low intakes of saturated and trans fat, low glycemic load, and adequate intakes of fruits and vegetables, cereal fiber, and unsaturated fat, especially omega-3 fatty acids), a healthy weight (body mass index <25 kg/m2), regular exercise, and moderate alcohol consumption.
Most of these environmental factors affect CVD risk by improving one’s general health status, including preventing infection and inflammation and reducing oxidative stress by bolstering antioxidant defenses. Compelling evidence now points to cardiovascular inflammation and resultant oxidative stress as important triggers in the complex chain of events leading to atherosclerosis.
Inflammation is a complicated process that develops in response to infection or injury.
Damaged tissue releases chemicals that attract white blood cells, which then attack microorganisms and consume damaged cells. During this process, hormone-like signaling molecules called cytokines are produced that accelerate inflammation. One cytokine, IL-6, stimulates the synthesis of C-reactive protein, which is a biomarker for inflammation .
A crucial initiating event in atherosclerosis is the interaction of white blood cells—monocytes and lymphocytes—with the endothelium, which is the cell layer of the blood vessel wall that faces the blood stream. Following adherence of these white blood cells to the endothelium, they migrate across the endothelium and into the arterial wall (see figure below). Once trapped in the arterial wall, the monocytes engorge oxidized (“bad”) cholesterol and are converted into fat-laden foam cells. Formation and aggregation of foam cells is the first manifestation of atherosclerosis, leading to the narrowing of the opening of the artery and, eventually, to full-blown CVD.
The adherence of monocytes to the endothelium and subsequent migration into the arterial wall are caused by presentation of “sticky” proteins called cellular adhesion molecules on the surface of endothelial cells. Inflammatory cytokines directly stimulate the production of these adhesion molecules. Furthermore, studies in patients and experimental animals have found that there is an abundance of adhesion molecules on arterial sites prone to atherosclerosis. For example, the very first change in the arterial wall in response to feeding rabbits a high-cholesterol diet is the presentation of adhesion molecules, even before foam cells and atherosclerotic lesions become discernable. Studies in mice have also found that genetic deficiencies of adhesion molecules are associated with significantly delayed atherosclerosis. Therefore, adhesion molecules may be an important target for the prevention and treatment of atherosclerosis and CVD.
What dietary or therapeutic agents might be able to block or inhibit production of endothelial adhesion molecules? Since regulation of these molecules has been related to inflammation and oxidative stress, antioxidants may exert inhibitory effects. To test this hypothesis, we investigated the role of three antioxidants—alpha-lipoic acid, glutathione, and vitamin C—in the production of adhesion molecules in cultured human endothelial cells and in mice.
Alpha-lipoic acid is a naturally occurring compound that appears to be useful in treating pathologies associated with oxidative stress. For example, alpha-lipoic acid has been safely used for more than 30 years in Europe to prevent and treat complications associated with diabetes, such as protein glycation, abnormal glucose utilization, polyneuropathy, and cataracts. Alpha-lipoic acid can also bind to, or chelate, metals like iron and copper. Exogenously supplied lipoic acid is readily absorbed by cells and tissues and then rapidly reduced to its potent antioxidant form, dihydrolipoate.
We found that alpha-lipoic acid significantly inhibits both the formation of adhesion molecules and the adherence of monocytes to endothelial cells in culture. However, to our surprise these processes were not influenced by vitamin C or glutathione, suggesting that general oxidative stress does not play a significant role in the activation of human endothelial cells to produce adhesion molecules. Because alpha-lipoic acid also is a good metal chelator, we hypothesized that metals may be involved in the production of adhesion molecules. To test this hypothesis, we added compounds to the cell culture that specifically chelate iron or copper. Our results showed that treatment with metal chelators also inhibits the production of adhesion molecules and monocyte adherence to cultured endothelial cells, thus supporting our hypothesis that the metal-chelating activity of alpha-lipoic acid may be responsible for its salubrious effects on endothelial cell function.
C-reactive protein, or CRP, is produced in the liver and has emerged as a strong predictor of clinical events of cardiovascular diseases, such as heart attacks and stroke, even in cases where cholesterol levels may be normal. For this reason, CRP assays may become a routine part of blood tests for determining CVD risk. CRP levels in the blood are normally undetectable or very low; high levels are strongly associated with inflammation. CRP is a biomarker for the metabolic disorder called syndrome X, type II diabetes, hypertension, and CVD, and is linked to body mass. CRP levels may be lowered by physical activity, anti-inflammatory drugs like aspirin, and through weight loss in obese individuals. Recent studies have detected CRP in atherosclerotic lesions, where it has been found to attract white blood cells called monocytes and to increase the production of adhesion molecules in endothelial cells (see accompanying article). Although few studies have investigated the relationship between antioxidants and CRP, a small study on patients with peripheral artery disease by Belgian researchers recently found that CRP levels in blood were inversely correlated with vitamin C levels.
This finding, along with other evidence on vitamin E, suggests that antioxidants may play an anti-inflammatory role.
(R)-alpha-lipoic acid reverses the age-associated increase in susceptibility of hepatocytes to tert-butylhydroperoxide both in vitro and in vivo.
Hepatocytes were isolated from young (3-5 months) and old (24-28 months) rats and incubated with various concentrations of tert-butylhydroperoxide (t-BuOOH). The t-BuOOH concentration that killed 50% of cells (LC50) in 2 hr declined nearly two-fold from 721 +/- 32 microM in cells from young rats to 391 +/- 31 microM in cells from old rats.
This increased sensitivity of hepatocytes from old rats may be due, in part, to changes in glutathione (GSH) levels, because total cellular and mitochondrial GSH were 37.7% and 58.3% lower, respectively, compared to cells from young rats. Cells from old animals were incubated with either (R)- or (S)-lipoic acid (100 microM) for 30 min prior to the addition of 300 microM t-BuOOH.
The physiologically relevant (R)-form, a coenzyme in mitochondria, as opposed to the (S)-form significantly protected hepatocytes against t-BuOOH toxicity. Dietary supplementation of (R)-lipoic acid [0.5% (wt/wt)] for 2 weeks also completely reversed the age-related decline in hepatocellular GSH levels and the increased vulnerability to t-BuOOH as well. An identical supplemental diet fed to young rats did not enhance the resistance to t-BuOOH, indicating that antioxidant protection was already optimal in young rats. Thus, this study shows that cells from old animals are more susceptible to oxidant insult and (R)-lipoic acid, after reduction to an antioxidant in the mitochondria, effectively reverses this age-related increase in oxidant vulnerability.
Attributes of CoQ10
Co Enzyme Q10 :
Ø functions as a strong antioxidant, retards the ageing process and has life extension potential.
Ø improves blood circulation.
Ø increases life expectancy of person’s afflicted with these forms of cancer - Breast cancer, lung cancer, laryngeal cancer, pancreatic cancer and Prostate cancer.
Ø can double the immune function within 24 hours - increasing the level of protective antibodies and resistance to viruses.
Ø improves athletic performance by increasing the production of efficient aerobic energy (ATP) within the mitochondria).
Ø increases Stamina and lowers free radical activity
Ø facilitates and balances the production of Insulin and Glucagon by the Pancreas.
Ø helps to conserve Vitamin E stores.
Ø reduces the severity of toxic side effects associated with the drug - Doxorubicin and also increases the potency of Doxorubicin in its ability to kill cancer cells by 200%.
Ø concentrates in vital organs such as the heart, liver, kidneys and pancreas.
Ø alleviates Asthma and Allergies
Ø alleviates Diabetes Mellitus (many of the complications are associated with Co Enzyme Q10 deficiency.
Ø dramatically halts the progression of Gingivitis and Periodontal Disease and can ameliorate the damage already done
Ø increases oxygen efficiency potential in the mitochondria and is an integral Co-Enzyme necessary for proper function of the E.T.S.( Electron Transport System) - aerobic system
Ø alleviates Obesity by reducing weight (where the deficiency of Co Q10 exists.
Ø helps to prevent the onset of Alzheimer’s Disease and Parkinson’s Disease.
Ø alleviates Multiple Sclerosis and Schizophrenia.
Ø is effective in promoting recovery from damage to auditory Hairs (Tininitis).
Ø Germanium and Selenium improve Co Enzyme Q10’s production.
Dosage of CoQ10
DOSAGE TYPES DOSAGE AMOUNT INFORMATION
General Dosage 30 mg per day Even younger people with no obvious CoQ10 deficiency are able to derive benefits by using 30 mg of supplemental CoQ10 per day in a single dose.
Maintenance Dosage 30 - 100 mg per day Studies involving humans have concluded that daily doses of at least 30 mg per day are required to significantly raise blood CoQ10 levels.
Therapeutic Dosage 60 - 500 mg per day Dosages of 100 mg per day or greater are normally administered in 2 or 3 divided doses.
Other Dosages 300 - 500 mg per day High dosages have been shown to retard the progression of some cancers.
Most people at 20 years of age can generally only supply 25% of their optimum needs of CoQ10 per day. The amount of CoQ10 produced by the body declines with increasing age, so that at 30 years your body produces 20% of your need, at 40 years only 15%, at 50 years only 12% and at 60 years your body produces only 10% of required needs.
Summary
Lipoic Acid
The body routinely converts some alpha-lipoic acid to dihydrolipoic acid, which appears to be an even more powerful antioxidant. Both forms of lipoic acid quench peroxynitrite radicals, an especially dangerous type consisting of both oxygen and nitrogen, according to a recent paper in FEBS Letters (Whiteman M, et al., FEBS Letters, 1996; 379:74-6). Peroxynitrite radicals play a role in the development of atherosclerosis, lung disease, chronic inflammation, and neurological disorders.
Alpha-lipoic acid also plays an important role in the synergism of antioxidants, what Packer prefers to call the body's "antioxidant network." It directly recycles and extends the metabolic lifespans of vitamin C, glutathione, and coenzyme Q10, and it indirectly renews vitamin E.
In Germany, alpha-lipoic acid is an approved medical treatment for peripheral neuropathy, a common complication of diabetes. It speeds the removal of glucose from the bloodstream, at least partly by enhancing insulin function, and it reduces insulin resistance, an underpinning of many cases of coronary heart disease and obesity. The therapeutic dose for lipoic acid is 600 mg/day. In the United States, it is sold as a dietary supplement, usually as 50 mg tablets. (The richest food source of alpha-lipoic acid is red meat.)
"From a therapeutic viewpoint, few natural antioxidants are ideal," Packer recently explained in Free Radical Biology & Medicine. "An ideal therapeutic antioxidant would fulfill several criteria. These include absorption from the diet, conversion in cells and tissues into usable form, a variety of antioxidant actions (including interactions with other antioxidants) in both membrane and aqueous phases, and low toxicity."
"Alpha-lipoic acid...is unique among natural antioxidants in its ability to fulfill all of these requirements," he continued, "making it a potentially highly effective therapeutic agent in a number of conditions in which oxidative damage has been implicated."
Coenzyme Q10
Over the past several years, there has been a steady increase in public interest and awareness of nutritional supplements and vitamins. Along with this accelerated interest has come an understandable explosion in the number and complexity of questions raised by patients about vitamins in general. By and large, these questions are quite difficult to answer. I personally am frequently asked the following questions:
1. What is CoQ10?
It is a fat-soluble vitamin-like substance present in every cell of the body and serves as a coenzyme for several of the key enzymatic steps in the production of energy within the cell. It also functions as an antioxidant which is important in its clinical effects. It is naturally present in small amounts in a wide variety of foods but is particularly high in organ meats such as heart, liver and kidney, as well as beef, soy oil, sardines, mackerel, and peanuts. To put dietary CoQ10 intake into perspective, one pound of sardines, two pounds of beef, or two and one half pounds of peanuts, provide 30 mg of CoQ10. CoQ10 is also synthesized in all tissues and in healthy individuals normal levels are maintained both by CoQ10 intake and by the body's synthesis of CoQ10. It has no known toxicity or side effects.
2. Should I take CoQ10?
This question can be asked in two ways. First, should a reasonably healthy person take CoQ10 to stay healthy or to become more robust?
At present I do not believe anyone knows the answer to this question.
Second, should a person with an illness such as congestive heart failure take CoQ10? As with any change in nutrition, diet, medication, or even activity, CoQ10 should be discussed with one's physician. As improvement in heart function occurs, a patient should have regular medical follow up with particular attention to concomitant drug therapy. The attached references will provide detailed information on the clinical use of CoQ10 and can be obtained from any good medical library.
3. What is the dosage of CoQ10?
The dosage of CoQ10 used in clinical trials has evolved over the past 20 years. Initially, doses as small as 30 to 45 mg per day were associated with measurable clinical responses in patients with heart failure. More recent studies have used higher doses with improved clinical response, again in patients with heart failure. Most studies with CoQ10 involve the measurement of the level of CoQ10 in blood.
CoQ10 shows a moderate variability in its absorption, with some patients attaining good blood levels of CoQ10 on 100 mg per day while others require two or three times this amount to attain the same blood level. All CoQ10 available today in the United States is manufactured in Japan and is distributed by a number of companies who place the CoQ10 either in pressed tablets, powder-filled capsules, or oil-based gelcaps. CoQ10 is fat-soluble and absorption is significantly improved when it is chewed with a fat-containing food. Published data on the dosage of CoQ10 relates almost exclusively to the treatment of disease states. There is no information on the use of CoQ10 for prevention of illness. This is an extremely important question which, to date, does not have an answer.
4. If CoQ10 is so effective in the treatment of heart failure, why is it not more generally used?
The answer to this question is found in the fields of politics and marketing and not in the fields of science or medicine. The controversy surrounding CoQ10 likewise is political and economic as the previous 30 years of research on CoQ10 have been remarkably consistent and free of major controversy. Although it is not the first time that a fundamental and clinically important discovery has come about without the backing of a pharmaceutical company, it is the first such discovery to so radically alter how we as physicians must view disease. While the pharmaceutical industry does a good job at physician and patient education on their new products, the distributors of CoQ10 are not as effective at this. This education is very costly and can only be done with the reasonable expectation of patent protected profit. CoQ10 is not patentable. The discovery of CoQ10 was based primarily on support from the National Heart Institute of NIH (National Institute of Health) at the Institute for Enzyme Research, University of Wisconsin.
THE FUTURE OF COENZYME Q10
In the past 50 years the driving force in medicine has been the development of drugs and procedures to modify the pathophysiology of illness. As viewed from the trenches of medical practice, the advances in drug therapy, although notable and clearly helpful, appear to have reached a plateau.
Most of the "new" drugs over the past several years are primarily variants of old drugs. By comparison, the impressive advances made by basic scientists, biochemists, and molecular biologists, are only now beginning to be appreciated by the medical profession, and the enormous potential of these basic science advances has yet to be pursued.
Chemical Abstracts
Clinical information from ncbi.nlm.nih.gov and other sources
Lipoic acid
: Altern Med Rev. 2007 Jun;12(2):113-45. Links
Osteoporosis: integrating biomarkers and other diagnostic correlates into the management of bone fragility.
McCormick RK.
Bone health, characterized by its mass, density, and micro-architectural qualities, is maintained by a balanced system of remodeling. The lack of these qualities, caused by an uncoupling of the remodeling process, leads to bone fragility and an increased risk for fracture. The prime regulator of bone remodeling is the RANK/RANKL/OPG system. The common origin of both bone and immune stem cells is the key to understanding this system and its relationship to the transcription factor nuclear factor kappaB in bone loss and inflammation. Via this coupled osteo-immune relationship, a catabolic environment from heightened proinflammatory cytokine expression and/or a chronic antigen-induced activation of the immune system can initiate a switch-like diversion of osteoprogenitor-cell differentiation away from monocyte-macrophage and osteoblast cell formation and toward osteoclast and adipocyte formation. This disruption in bone homeostasis leads to increased fragility. Dietary and specific nutrient interventions can reduce inflammation and limit this diversion. Common laboratory biomarkers can be used to assess changes in body metabolism that affect bone health. This literature review offers practical information for applying effective strategic nutrition to fracture-risk individuals while monitoring metabolic change through serial testing of biomarkers. As examples, the clinician may recommend vitamin K and potassium to reduce hypercalciuria, _-lipoic acid and N-acetylcysteine to reduce the bone resorption marker N-telopeptide (N-Tx), and dehydroepiandrosterone (DHEA), whey, and milk basic protein (the basic protein fraction of whey) to increase insulin-like growth factor-1 (IGF-1) and create a more anabolic profile.
PMID: 17604458 [PubMed - indexed for MEDLINE]
Biosci Rep. 2007 Jun;27(1-3):53-67. Links
Functional diagnostics in mitochondrial diseases.
Siciliano G, Volpi L, Piazza S, Ricci G, Mancuso M, Murri L.
Department of Neuroscience, Section of Neurology, University of Pisa, Via Roma 67, 56126, Pisa, Italy. g.siciliano@med.unipi.it
Mitochondrial diseases (MD) with respiratory chain defects are caused by genetic mutations that determine an impairment of the electron transport chain functioning. Diagnosis often requires a complex approach with measurements of serum lactate, magnetic resonance spectroscopy (MRS), muscle histology and ultrastructure, enzymology, genetic analysis, and exercise testing. The ubiquitous distribution of the mitochondria in the human body explains the multiple organ involvement. Exercise intolerance is a common symptom of MD, due to increased dependence of skeletal muscle on anaerobic metabolism, with an excess lactate generation, phosphocreatine depletion, enhanced free radical production, reduced oxygen extraction and electron flux through the respiratory chain. MD treatment has included antioxidants (vitamin E, alpha lipoic acid), coenzyme Q10, riboflavin, creatine monohydrate, dichloroacetate and exercise training. Exercise is a particularly important tool in diagnosis as well as in the management of these diseases.
PMID: 17492503 [PubMed - indexed for MEDLINE]
Expert Opin Investig Drugs. 2007 Mar;16(3):291-302. Links
Alpha-lipoic acid: physiologic mechanisms and indications for the treatment of metabolic syndrome.
Pershadsingh HA.
Bethesda Pharmaceuticals, Inc., 404 Windsor Park Drive, Bakersfield, California 93311, USA. hpershad@UCI.edu
In animal experiments, the potent antioxidant and free radical scavenger alpha-lipoic acid has been shown to cause weight loss, ameliorate insulin resistance and atherogenic dyslipidemia, as well as to lower blood pressure, all of these being components of the metabolic syndrome. Recent investigations on its mechanisms of action indicate that alpha-lipoic acid can affect central and peripheral modulation of 5'-AMP-activated protein kinase, activate PPAR-alpha and PPAR-gamma, modulate PPAR-regulated genes and upregulate the expression of PPAR-gamma mRNA and protein in cardiac tissue and aorta smooth muscle. To a large extent, these findings can explain the observed beneficial metabolic effects of alpha-lipoic acid, supporting its potential application as a therapeutic agent for the treatment of the metabolic syndrome.
PMID: 17302524 [PubMed - indexed for MEDLINE]
Mini Rev Med Chem. 2006 Nov;6(11):1269-74. Links
Lipoic acid, a lead structure for multi-target-directed drugs for neurodegeneration.
Bolognesi ML, Minarini A, Tumiatti V, Melchiorre C.
Department of Pharmaceutical Sciences, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Nowadays, drug discovery based on a single-target-directed strategy seems inappropriate for the treatment of complex diseases that have multiple pathogenic factors. Recent research into new drugs, which are able to hit different targets, highlights the idea that a single molecule could be sufficient to treat multi-factorial diseases. In this review, examples of multi-target-directed compounds derived from lipoic acid are examined.
PMID: 17100639 [PubMed - indexed for MEDLINE]
Pharmacol Rep. 2005 Sep-Oct;57(5):570-7. Links
Lipoic acid - the drug of the future?
Bilska A, Wlodek L.
Institute of Medical Biochemistry, Medical College, Jagiellonian University, Kopernika 7, PL 31-034 Kraków, Poland.
Numerous experimental and clinical studies proved efficiency of treatment with lipoic acid-containing drugs in diseases, in which pro- and antioxidant balance is disrupted (diabetes, neurodegenerative diseases, acquired immune deficiency syndrome (AIDS), tumors, etc.). Efficiency of lipoate has been attributed to unique antioxidant properties of lipoate/dihydrolipoate system, its reactive oxygen species (ROS) scavenging ability and significant effect on the tissue concentrations of reduced forms of other antioxidants, including one of the most powerful, glutathione (thus lipoate is called an antioxidant of antioxidants). Moreover, analysis of literature data suggests participation of lipoic acid in processes of cell growth and differentiation. This fact can be crucial to clinical practice, however, this problem requires further studies.
PMID: 16227639 [PubMed - indexed for MEDLINE]
Pharmacol Ther. 2007 Jan;113(1):154-64. Epub 2006 Sep 20. Links
Lipoic acid as a novel treatment for Alzheimer's disease and related dementias.
Holmquist L, Stuchbury G, Berbaum K, Muscat S, Young S, Hager K, Engel J, Münch G.
Department of Biochemistry and Molecular Biology and Comparative Genomics Centre, School of Pharmacy and Molecular Sciences, James Cook University, Townsville, Australia.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that destroys patient memory and cognition, communication ability with the social environment and the ability to carry out daily activities. Despite extensive research into the pathogenesis of AD, a neuroprotective treatment - particularly for the early stages of disease - remains unavailable for clinical use. In this review, we advance the suggestion that lipoic acid (LA) may fulfil this therapeutic need. A naturally occurring precursor of an essential cofactor for mitochondrial enzymes, including pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH), LA has been shown to have a variety of properties which can interfere with pathogenic principles of AD. For example, LA increases acetylcholine (ACh) production by activation of choline acetyltransferase and increases glucose uptake, thus supplying more acetyl-CoA for the production of ACh. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals and also scavenges reactive oxygen species (ROS), thereby increasing the levels of reduced glutathione. Via the same mechanisms, downregulation redox-sensitive inflammatory processes is also achieved. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein. The reduced form of LA, dihydrolipoic acid (DHLA), is the active compound responsible for most of these beneficial effects. R-alpha-LA can be applied instead of DHLA, as it is reduced by mitochondrial lipoamide dehydrogenase, a part of the PDH complex. In this review, the properties of LA are explored with particular emphasis on how this agent, particularly the R-alpha-enantiomer, may be effective to treat AD and related dementias.
PMID: 16989905 [PubMed - indexed for MEDLINE]
Lipoic acid as a novel treatment for Alzheimer's disease and related dementias
Lina Holmquista, Grant Stuchburya, Katrin Berbauma, Sonja Muscata, Simon Youngb, Klaus Hagerc, Jürgen Engeld and Gerald Müncha, ,
aDepartment of Biochemistry and Molecular Biology and Comparative Genomics Centre, School of Pharmacy and Molecular Sciences, James Cook University, Townsville, Australia
bDiscipline of Pharmacy, School of Pharmacy and Molecular Sciences, James Cook University, Townsville, Australia
cKlinik für Medizinische Rehabilitation und Geriatrie der Henriettenstiftung, Hannover, Germany
dZentaris GmbH, Frankfurt am Main, Germany
Available online 20 September 2006.
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that destroys patient memory and cognition, communication ability with the social environment and the ability to carry out daily activities. Despite extensive research into the pathogenesis of AD, a neuroprotective treatment – particularly for the early stages of disease – remains unavailable for clinical use. In this review, we advance the suggestion that lipoic acid (LA) may fulfil this therapeutic need. A naturally occurring precursor of an essential cofactor for mitochondrial enzymes, including pyruvate dehydrogenase (PDH) and a-ketoglutarate dehydrogenase (KGDH), LA has been shown to have a variety of properties which can interfere with pathogenic principles of AD. For example, LA increases acetylcholine (ACh) production by activation of choline acetyltransferase and increases glucose uptake, thus supplying more acetyl-CoA for the production of ACh. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals and also scavenges reactive oxygen species (ROS), thereby increasing the levels of reduced glutathione. Via the same mechanisms, downregulation redox-sensitive inflammatory processes is also achieved. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein. The reduced form of LA, dihydrolipoic acid (DHLA), is the active compound responsible for most of these beneficial effects. R-a-LA can be applied instead of DHLA, as it is reduced by mitochondrial lipoamide dehydrogenase, a part of the PDH complex. In this review, the properties of LA are explored with particular emphasis on how this agent, particularly the R-a-enantiomer, may be effective to treat AD and related dementias.
Keywords: Alzheimer's disease; Dementia; Neuroprotection; Metal chelator; Antioxidant; Lipoic acid
Abbreviations: ACh, acetylcholine; AD, Alzheimer's disease; DHLA, dihydrolipoic acid; LA, lipoic acid (when the stereoisomer is not specifically mentioned, refers to the racemic mixture); ROS, reactive oxygen species
Arch Gerontol Geriatr. 2006 May-Jun;42(3):289-306. Epub 2006 Jan 26. Links
Menopause: a review on the role of oxygen stress and favorable effects of dietary antioxidants.
Miquel J, Ramírez-Boscá A, Ramírez-Bosca JV, Alperi JD.
Department of Biotechnology, University of Alicante, San Vicente, Ap. 99, E-03080 Alicante, Spain.
Menopause is often accompanied by hot flashes and degenerative processes such as arteriosclerosis and atrophic changes of the skin that suggest an acceleration of aging triggered by estrogen lack. Therefore, hormone replacement therapy (HRT) has been considered the most suitable treatment for the above symptoms and processes. However, because of the possible serious side effects of HRT (especially the increased risk of thrombo-embolic accidents and breast cancer) there is a growing demand for alternative treatments of the symptoms and pathological processes associated with menopause. In agreement with the above, we review research that supports the concept that oxygen stress contributes to menopause and that some of its physiopathological effects may be prevented and/or treated improving the antioxidant defense of menopausic and postmenopausic women. Accordingly, a selection of micronutrients may be useful as a dietary supplement for protection against the decline of physiological functions caused by age-related oxygen stress. Since aging is accompanied by a progressive oxidation of the physiological sulfur pool, we emphasize the role of the vitamins B that help to maintain the GSH/GSSG ratio in its normal reduced state. Nutritional supplements should also include the key antioxidant vitamins C and E, as well as beta-carotene and the mineral micronutrients found in the oxygen radical-detoxifying enzymes glutathione peroxidase and superoxide dismutase. Moreover, the reviewed data suport the concept that other antioxidants such as lipoic acid and the precursors of glutathione thioproline (TP) and l-2-oxothiazolidine-4-carboxylic acid (OTC), as well as the soy isoflavones and the "coantioxidants" of an hydroalcoholic extract of Curcuma longa may help to prevent antioxidant deficiency with resulting protection of mitochondria against premature oxidative damage with loss of ATP synthesis and especialized cellular functions. Therefore, the administration under medical advice of synergistic combinations of some of the above mentioned antioxidants in the diet as well as topically (for skin protection) may have favorable effects on the health and quality of life of women, especially of those who cannot be treated with HR, suffer high levels of oxygen stress, and do not consume a healthy diet that includes five daily rations of fresh fruit and vegetables.
PMID: 16442644 [PubMed - indexed for MEDLINE]
Postepy Hig Med Dosw (Online). 2005;59:535-43. Links
[Lipoic acid: characteristics and therapeutic application]
[Article in Polish]
Malinska D, Winiarska K.
Zaklad Regulacji Metabolizmu, Instytut Biochemii, Uniwersytet Warszawski.
Lipoic acid (LA) and its reduced form dihydrolipoic acid (DHLA, are present in all prokaryotic and eukaryotic cells. Lipoic acid was once considered a vitamin, but now it is commonly accepted that it can be synthesized de novo in human cells. LA has long been known as a coenzyme of multienzymatic complexes catalyzing the decarboxylation of alpha-ketoacids, but the present investigations are focused on its antioxidative properties. Both LA and DHLA have proved to be potent free radicals scavengers and metal chelators. They are also responsible for the regeneration of active forms of other cellular antioxidants, including vitamins C and E. Moreover, lipoic acid is involved in the regulation of carbohydrate and lipid metabolism. LA is easily absorbed from the gastrointestinal tract, is able to cross the blood-brain barrier, and does not exhibit any serious side effects. All these features make lipoic acid a very promising drug. Nowadays, this compound is used in the treatment of diabetic neuropathy, fungi, and metal poisoning, as well as in liver disorders. The application of lipoic acid in treating other diseases, including hypertension and autoimmunological disorders, needs careful evaluation.
PMID: 16407792 [PubMed - indexed for MEDLINE]
J Cardiovasc Nurs. 2006 Jan-Feb;21(1):9-16. Links
Supplemental conditionally essential nutrients in cardiovascular disease therapy.
Kendler BS.
Dept. of Biology, CMSV Campus, Manhattan College, Riverdale, NY 10471, USA. barry.kendler@mountsaintvincent.edu
Conditionally essential nutrients (CENs) are organic compounds that are ordinarily produced by the body in amounts sufficient to meet its physiological requirements. However, in disorders, such as cardiovascular disease (CVD), and in other physiologically stressful conditions, their biosynthesis may be inadequate. Under these circumstances, CENs become essential nutrients, comparable to vitamins. The CENs of primary importance in CVD, based on the quantity and quality of human clinical studies, are l-arginine, l-carnitine, propionyl-l-carnitine, and coenzyme Q10. Controlled studies of these CENs are reviewed in depth. Taurine is a CEN of secondary importance caused by a limited human database. Other putative CENs include alpha-lipoic acid, betaine, chondroitin sulfate, glutamine, and d-ribose, each of which is mentioned in passing. Collectively, CENs have demonstrated favorable clinical effects in CVDs, including chronic heart failure, myocardial infarction, angina pectoris, and in CVD risk factors, such as hypertension, hyperlipidemia, and lipoprotein(a). Limited research has pointed to possible benefits in CVD therapy accruing from supplementation with several CENs in combination. Additional controlled clinical studies of CENs in CVD are urgently needed. In view of the efficacy and safety of appropriate supplementation with CENs, it is strongly suggested that healthcare professionals become knowledgeable of these potentially important additions to the CVD therapeutic armamentarium.
PMID: 16407731 [PubMed - indexed for MEDLINE]
Chem Biol Interact. 2006 Mar 10;160(1):1-40. Epub 2006 Jan 23. Links
Free radicals, metals and antioxidants in oxidative stress-induced cancer.
Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M.
Faculty of Chemical and Food Technology, Slovak Technical University, SK-812 37 Bratislava, Slovakia. marian.valko@stuba.sk
Oxygen-free radicals, more generally known as reactive oxygen species (ROS) along with reactive nitrogen species (RNS) are well recognised for playing a dual role as both deleterious and beneficial species. The "two-faced" character of ROS is substantiated by growing body of evidence that ROS within cells act as secondary messengers in intracellular signalling cascades, which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. The cumulative production of ROS/RNS through either endogenous or exogenous insults is termed oxidative stress and is common for many types of cancer cell that are linked with altered redox regulation of cellular signalling pathways. Oxidative stress induces a cellular redox imbalance which has been found to be present in various cancer cells compared with normal cells; the redox imbalance thus may be related to oncogenic stimulation. DNA mutation is a critical step in carcinogenesis and elevated levels of oxidative DNA lesions (8-OH-G) have been noted in various tumours, strongly implicating such damage in the etiology of cancer. It appears that the DNA damage is predominantly linked with the initiation process. This review examines the evidence for involvement of the oxidative stress in the carcinogenesis process. Attention is focused on structural, chemical and biochemical aspects of free radicals, the endogenous and exogenous sources of their generation, the metal (iron, copper, chromium, cobalt, vanadium, cadmium, arsenic, nickel)-mediated formation of free radicals (e.g. Fenton chemistry), the DNA damage (both mitochondrial and nuclear), the damage to lipids and proteins by free radicals, the phenomenon of oxidative stress, cancer and the redox environment of a cell, the mechanisms of carcinogenesis and the role of signalling cascades by ROS; in particular, ROS activation of AP-1 (activator protein) and NF-kappaB (nuclear factor kappa B) signal transduction pathways, which in turn lead to the transcription of genes involved in cell growth regulatory pathways. The role of enzymatic (superoxide dismutase (Cu, Zn-SOD, Mn-SOD), catalase, glutathione peroxidase) and non-enzymatic antioxidants (Vitamin C, Vitamin E, carotenoids, thiol antioxidants (glutathione, thioredoxin and lipoic acid), flavonoids, selenium and others) in the process of carcinogenesis as well as the antioxidant interactions with various regulatory factors, including Ref-1, NF-kappaB, AP-1 are also reviewed.
PMID: 16430879 [PubMed - indexed for MEDLINE]
Annu Rev Pharmacol Toxicol. 2004;44:239-67. Links
The role of oxidative stress in carcinogenesis.
Klaunig JE, Kamendulis LM.
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. jklauni@iupui.edu
Chemical carcinogenesis follows a multistep process involving both mutation and increased cell proliferation. Oxidative stress can occur through overproduction of reactive oxygen and nitrogen species through either endogenous or exogenous insults. Important to carcinogenesis, the unregulated or prolonged production of cellular oxidants has been linked to mutation (induced by oxidant-induced DNA damage), as well as modification of gene expression. In particular, signal transduction pathways, including AP-1 and NFkappaB, are known to be activated by reactive oxygen species, and they lead to the transcription of genes involved in cell growth regulatory pathways. This review examines the evidence of cellular oxidants' involvement in the carcinogenesis process, and focuses on the mechanisms for production, cellular damage produced, and the role of signaling cascades by reactive oxygen species.
PMID: 14744246 [PubMed - indexed for MEDLINE]
Ukr Biokhim Zh. 2005 May-Jun;77(3):20-6. Links
[Alpha-lipoic--dihydrolipoic acids--active bioantioxidant and bioregulatory system]
[Article in Russian]
Baraboi VA.
alpha-Lipoic (LA) acid (thioctic acid) is an intramolecular disulfide that may be simply endogenically turned into dithiol. Dihydrolipoic acid (DHLA)/ LA and DHLA are bioantioxidants. They are synthesized in the body and taken with diet. Water- and lipide-soluble LA is highly-effective against the reactive oxygen species. LA (DHLA) protect the biomembranes, mitochondria from oxidative stresses of various kinds. LA, DHLA and lipoamide function as cofactors of polyenzyme mitochondrial complexes of 2-oxoacid dehydrogenases, of glycin decarboxylases and of some other enzymes. LA (DHLA) is ubiquinone reactivator and synergist by vitamin A, C, E. LA optimizes glucose metabolism, it is effective in insulin-resistant diabetes and its complications, in neutopathies and neurodegenerative diseases. PMID: 16566124 [PubMed - indexed for MEDLINE]
Postgrad Med J. 2006 Feb;82(964):95-100. Links
Diabetic neuropathy.
Bansal V, Kalita J, Misra UK.
Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareilly Road, Lucknow 226014, India.
Diabetic neuropathy (DN) refers to symptoms and signs of neuropathy in a patient with diabetes in whom other causes of neuropathy have been excluded. Distal symmetrical neuropathy is the commonest accounting for 75% DN. Asymmetrical neuropathies may involve cranial nerves, thoracic or limb nerves; are of acute onset resulting from ischaemic infarction of vasa nervosa. Asymmetric neuropathies in diabetic patients should be investigated for entrapment neuropathy. Diabetic amyotrophy, initially considered to result from metabolic changes, and later ischaemia, is now attributed to immunological changes. For diagnosis of DN, symptoms, signs, quantitative sensory testing, nerve conduction study, and autonomic testing are used; and two of these five are recommended for clinical diagnosis. Management of DN includes control of hyperglycaemia, other cardiovascular risk factors; alpha lipoic acid and L carnitine. For neuropathic pain, analgesics, non-steroidal anti-inflammatory drugs, antidepressants, and anticonvulsants are recommended. The treatment of autonomic neuropathy is symptomatic.
PMID: 16461471 [PubMed - indexed for MEDLINE]
Inhibition of NF-kappa B DNA binding by alpha-lipoic acid.
Suzuki YJ, Packer L.
Int Conf AIDS. 1994 Aug 7-12; 10: 27 (abstract no. 401A).
Department of Molecular & Cell Biology, University of California, Berkeley 94720.
NF-kappa B transcription factor regulates HIV activation. Natural and safe compounds which target NF-kappa B action may, therefore, be useful in AIDS therapy to support the actions of antiviral agents. We previously found that alpha-lipoic acid (6,8-dithio-octanoic acid) inhibits NF-kappa B activity induced by tumor necrosis factor (TNF), phorbol esters or HTLV Tax protein in cultured T cells. The present study compared the effects of lipoic acid homologues on NF-kappa B DNA binding activity in vivo and in vitro using band-shift assay. The addition of alpha-lipoic acid in the binding reaction mixtures containing nuclear extracts from stimulated T cells caused inhibition of NF-kappa B DNA binding in vitro. Octanoic acid which lacks the cyclic disulfide also inhibited DNA binding, suggesting that hydrocarbon chain participates in the mechanism of alpha-lipoic acid action. On the other hand, tetranorlipoic acid (2,4-dithio-butanoic acid), which lacks the hydrocarbon chain, was found to be more potent in inhibiting NF-kappa B DNA binding both in vitro and in vivo in TNF-stimulated Jurkat cells. Bisnorlipoic acid (4,6-dithio-hexanoic acid) was found to be less effective than tetranorlipoic acid; moreover, it never caused a complete inhibition of TNF-induced NF-kappa B activity in vivo. This suggests that tetranorlipoic acid affects NF-kappa B action through a distinct mechanism which is suppressed by hydrocarbon chain. Thus, the alpha-lipoic acid molecule contains two structures which can inhibit NF-kappa B action: (1) hydrocarbon chain tail which requires high concentrations and (2) cyclic disulfide head which is potent and whose inhibitory action is suppressed by hydrocarbon chain. Since alpha-lipoic acid is metabolized to tetranorlipoic acid in physiological systems, the dual mechanism of alpha-lipoic acid action may constitute its potential for HIV chemotherapy.
