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硫辛酸.Alpha-lipoic acid

INTRODUCTION:

Thioctic acidBelongs to( water-solubility) the vitamin, the human body may voluntarily produce; Besides can assist the human body the energy metabolism function, also can assist to resist the free radical the attack, prevents in vivo protein, low density cholesterol LDL and the DNA peroxidation destruction. In addition, the thioctic acid has also acted the extremely special role in the human body, pointed out according to the memoir, the thioctic acid anti- oxidized effect is extremely unique, it certainly does not like the common oxidation inhibitor only to have to the specific object or certain spots has the anti- oxidized effect, it in vivo may say is any oxidation inhibitor "the generation hits", when the human body lacks vitamin C or vitamin E, if in vivo includes the foot enough thioctic acid, then may temporarily replace their work; The thioctic acid also may strengthen vitamin C and the vitamin E potency; Therefore the thioctic acid existence has adds while the effect regarding the anti- oxidation. Moreover the supplement thioctic acid also can strengthen other oxidation inhibitor like vitamin C, E and CoQ10 and so on the use factor, can handle the enhancement whole anti- oxidized ability, especially, be able to resist when the grain of line body use oxygen produces the free radical, is the best grain of line body oxidation inhibitor. Therefore, the thioctic acid is called the multi-purpose oxidation inhibitor.

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

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 avoide possible hypoglycemia.

ADVERSE REACTIONS

To date, alpha-lipoic acid in doses up to 600 milligrams daily has been well tolerated.

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.

METHODS:

Thioctic acid lipoic acid is the participationCitric acid circulation (citric acid cyclie, TCA cycle, Kreb cycle) important auxiliary factor

Natural lipoic acid is R- (+) -lipoic acid may turn the translated work Dextrorotation Thioctic acid but Laevo rotatory The thioctic acid is mostly is its laevo rotatory and the dextrorotation which the manual synthesis general chemical synthesis method obtained thioctic acid trades respectively occupies one half mixes the cooperation (racemic mixture)

Lipoic acid or α-lipoic acid has formula C₈H₁₄S₂O₂ and systematic name 5-(1,2-dithiolan-3-yl)pentanoic acid.

Dihydrolipoic acid or reduced lipoic acid has formula C₈H₁₆S₂O₂ and systematic name 6,8-disulfanyloctanoic acid. It is sometimes called lipoic acid.

Thioctic acid and dihydrothioctic acid are synonyms respectively.

Lipoic acid is a coenzyme in the oxoglutarate dehydrogenase complex of the citric acid cycle. It is involved in oxidative decarboxylations of keto and is presented as a growth factor for some organisms.

Lipoic acid exists as two enantiomers, the R-enantiomer and the S-enantiomer. Normally only the R-enantiomer of an amino acid is biologically active, but for lipoic acid the S-enantiomer assists in the reduction of the R-enantiomer when a racemic mixture is give 

Alpha Lipoic Acid Functions as a Universal Antioxidant and Free Radical Scavenger

Once inside cells, alpha-lipoic acid is converted to its more potent form, dihydrolipoic acid. Alpha lipoic acid is unique in that, like vitamin C, it is effective as an antioxidant in water based tissues such as the blood, and yet as clihydrolipoic acid it also is effective in protecting fatty tissues and membranes, a role it shares with vitamin E.

Thus alpha lipoic acid and clihydrolipoic acid together function as a universal antioxidant, meaning an antioxidant that quenches free radicals in both lipid and water-soluble portions of tissues and cells. Lipoic acid and clihydrolipoic acid are extremely powerful quenchers of hydroxyl, singlet-oxygen, peroxynitrite and other free radicals.'

Free radicals are associated with the development of atherosclerosis, lung disease, and neurological disorders, as well as being implicated in chronic inflammation, such as that found with rheumatoid arthritis and inflammatory bowel disease. Smog and many other sources of environmental toxins either are themselves or lead to the creation of free radicals in the body. 

Alpha Lipoic Acid Recycles Both Fat-and Water-Soluble Vitamins

Dihydrolipoic acid, which the body routinely manufactures from alpha lipoic acid, functions as a powerful direct chain breaking antioxidant and it enhances the antioxidant potency of other antioxidants (e.g., vitamins C and E) in both the water-based and lipid or non-water-based portions of cells.' Alpha lipoic acid directly recycles vitamin C and indirectly recycles vitamin E. This ability is unique and highly significant.

Several other unusual properties are characteristic of alpha-lipoic acid's universal antioxidant properties. Alpha lipoic acid increases glutathione levels in cells, at least in part, by improving the body's ability to use the amino acid L-cysteine to synthesize its supply of glutathione. Supplemental lipoic acid also maintains a normal ratio of reduced-to-oxidized coenzyme Q10. Coenzyme Q10 is especially important to the health of the mitochondria, the energy factories of the cells.

As a further benefit, alpha lipoic acid as clihydrolipoic acid is one of the very few antioxidant molecules (it may be the only one) small enough to penetrate the mitochondria directly. The reduction of alpha lipoic acid to clihydrolipoic acid and the role of alpha lipoic acid in the production of glutathione appear to be normal functions of alpha lipoic acid in the body. These are two of its several vitamin-like physiologic functions. 

What difference does this make to the form of lipoic acid you choose? Simple. Remember, R(+)-Lipoic Acid is the form of the molecule actually used by your body. R(+)-lipoic acid, and not the S(-)-form is made by your mitochondria, and is essential to their function. So it's no surprise that the mitochondrial enzyme complex (PDH) which is specifically responsible for converting lipoic acid into DHLA "prefers" the orthomolecular R(+)-enantiomer to the foreign S(-)-form: R(+)-Lipoic Acid is the "key" made by your body to open this "lock," while the S(-)-form is a badly-made copy.

In fact, the mitochondrial PDH enzyme complex converts R(+)-Lipoic Acid into DHLA at a rate at least twenty-four times faster than the S(-)-form. 37 38 , In some human cell types, the mitochondrial enzyme won't accept S(-)-lipoic acid at all. 38 Worse: at high concentrations the S(-)-enantiomer actually interferes with the mitochondrial enzyme's ability to make DHLA from R(+)-lipoic acid! 37 Fortunately, it's unlikely that anyone taking racemate lipoic acid supplements is in danger of getting such high concentrations of the S(-)-enantiomer into their bodies.

There are, however, places other than the mitochondria where the body can make some DHLA from either form of lipoic acid. As a result, when you look at the total DHLA formed in the cell, as opposed to just what's made in the PDH complex, the S(-)-enantiomer is still clearly inferior to the R(+)-, but the gulf is not quite so extreme: in the heart, for instance, R(+)-Lipoic Acid is "only" transformed into DHLA six to eight times more quickly than is the S(-)-form. 39

Even this, however, makes the S(-)-form look more useful than it really is, because the main way that the S(-)-form gets powered up into DHLA is by hijacking the activity of an enzyme which was never designed for the purpose: glutathione reductase. You may know glutathione (GSH) as another player in the antioxidant network , which is known specifically for its ability to protect the liver against toxins and drugs and to fight lung infections. 40 Glutathione reductase is an enzyme whose purpose is to recycle used-up glutathione (GSH) into its active form.

Well, there's only so much an enzyme can do at a time! Every moment that glutathione reductase is kept sidetracked by S(-)-lipoic acid is a moment during which it can't do the job it was designed to do - namely, again, to keep glutathione cycling smoothly through the cell's defense system. So when S(-)-lipoic acid takes over this enzyme, a bit more DHLA is made ?but a bit less glutathione is recycled, too. Bottom line: the S(-)-enantiomer robs Peter (GSH) to pay Paul (DHLA), giving with one hand while taking with the other. It's one step forward, one step back. R(+)-Lipoic Acid has no such problems, being strongly taken up by the mitochondrial enzyme as it was designed to do, and having a much weaker tendency to waste glutathione reductase's time.

But enough molecular babble (for now!). What does all of this mean, in terms of real-world antioxidant defense? Scientists have been asking themselves this question for some time, and have made some discoveries that users of lipoic acid need to know about. Let's have a look at their findings.

One study 41 looked at the effects of aging - and of the two forms of lipoic acid - on the vulnerability of liver cells to tert-butylhydroperoxide (t-BuOOH), a chemical that causes the cell's mitochondria to churn out more free radicals. As had been seen in other studies, older animals' cells were much more susceptible to the toxin than were those from young animals: an amount of t-BuOOH that half of the cells from young animals managed to survive, was enough to kill all but 12% of the cells from older ones.

Astoundingly, when the cells of old animals were given one of the two forms of lipoic acid in advance of t-BuOOH, R(+)-Lipoic Acid completely protected the cells from the free radical assault, so that the cells given R(+)-Lipoic Acid and the toxin survived as often as did cells which were not given the toxin at all. And, on the opposite extreme, S(-)-lipoic acid provided no significant protection against rampaging free radicals, such that cells were equally doomed by the toxin whether or not they also got the S(-)-form.

In another study 42 nerve cells from different parts of the brain were exposed to enough buthionine sulfoxamine (BSO) to destroy half of them. (BSO is a chemical that makes cells more vulnerable to free radicals by depleting the cell of antioxidant defenses). Providing the cells with R(+)-Lipoic Acid saved between one half and one third of the brain cells that would otherwise have died from necrotic cell death (depending on what kind of brain cells were involved). By contrast, neither the S(-)-form, nor the racemate (R,S)-lipoic acid found in common supplements, offered any significant protection.

The ineffectiveness of S(-)-lipoic acid is not terribly surprising, granted that the body converts so little of the artificial enantiomer into DHLA as compared with what's achieved using R(+)-lipoic acid. But it's surprising to see the impotence displayed by the racemate. After all, (R,S)-lipoic acid contains 50% R(+)-Lipoic Acid by weight ?and yet the presence, in the racemate, of an equal amount of the S(-)-enantiomer not only failed to lend a helping hand to the R(+)-Lipoic Acid which is present in the racemate, but actually rendered the racemate useless in protecting cells from a toxin against which R(+)-Lipoic Acid alone provides an effective shield! But we've already seen a couple of reasons why this might happen. The S(-)-form could have interfered with the supercharging of R(+)-Lipoic Acid to DHLA; it could also have further contributed to the imbalance in antioxidant defense created by BSO, by interfering with the recycling of glutathione.

Even more unexpected results were seen when the same research team decided to find out how much of the racemic form of lipoic acid, or of each of the two enantiomers, is needed to protect nerve cells against homocysteic acid, a byproduct of the toxic amino acid homocysteine. 42 It was no surprise when the scientists found that the R(+)-Lipoic Acid was able to protect nerve cells from the cortex of the brain against homocysteic acid at less than half (38%) of the concentration required by the S(-)-form. What was a surprise was the finding that the racemate was not only less potent than R(+)-lipoic acid, but was even weaker than the S(-)-enantiomer in protecting against this toxin! In fact, it took six and a half times as much of the racemate as had been needed by R(+)-Lipoic Acid to provide the same level of protection.

Also strange was the fact that the three forms of lipoic acid were about equally effective in protecting nerve cells from a different part of the brain (the hippocampus) against this toxin. 42 Then there are the results of experiments testing the ability of the different lipoic acid in protecting the lenses of lab animals' eyes from treatment with BSO. 29 All of the animals given the toxin by itself developed cataracts. Providing the animals R(+)-Lipoic Acid slashed the number of animals that developed cataracts by nearly half, to just 55% of the group, while the same amount of the S(-)-form provided no protection. Yet the protection afforded by an equal amount of the racemate was not significantly different from what was seen with R(+)-lipoic acid.

Clearly, different forms of lipoic acid vary in their protective powers, depending on the part of the body under attack and the nature of the threat. But it's also clear that, overall, R(+)-Lipoic Acid is far superior to both the S(-)-enantiomer, and the (R,S)-form available in common "lipoic acid" supplements in providing antioxidant protection. Indeed, when you find out about results like these, the S(-)-lipoic acid that's taking up half of your supplement starts to look more and more like the worst kind of "third wheel."