What is Lipoic acid used for?

Indications

Alpha-lipoic acid (Lipoic acid) is a caprylic acid-derived antioxidant. The compound is synthesized in the mitochondria and is a cofactor in the enzymatic nutrient breakdown. Lipoic acid is also available in red meat, beets, carrots, potatoes, spinach, and broccoli. Lipoic acid consists of a dithiol functional group that eliminates reactive oxygen species (ROS) by reducing the oxidized forms of other antioxidants. The organosulfur compound was discovered in 1937 when scientists found a type of bacteria that uses potato juice for reproduction. Lipoic acid has recently gained a reputation as an antioxidant. In the reduced form, dihydrolipoate reacts and neutralizes ROS, such as superoxide radicals, singlet oxygen, and hydroxyl radicals. Thus, Lipoic acid is highly beneficial in several oxidative-stress-associated conditions such as ischemia-reperfusion or radiation injury. [1]

Secondly, numerous studies have strongly supported the role of Lipoic acid in treating diabetic neuropathy. Lipoic acid does so by enhancing nitric oxide-mediated endothelium-dependent vasodilation, improving microcirculation in patients with diabetic polyneuropathy. Additionally, when taken with avocado or soybean unsaponifiable compounds, Lipoic acid is shown to significantly suppress prostaglandin E-2 production, a key cytokine in the pathogenesis of inflammation. Lipoic acid possesses an excellent iron-chelation property. The thiol groups in Lipoic acid are responsible for chelating irons. By increasing the glutathione levels inside the cells, Lipoic acid and dihydrolipoate excrete toxins, especially toxic metals, into the body. Lipoic acid preferentially binds to Zn, Pb, and Cu. On the other hand, dihydrolipoate forms complexes with Fe, Zn, Hg, Pb, and Cu. So far, Lipoic acid has the most substantial evidence of the therapeutic effect in diabetic neuropathy and oxidative stress conditions. There is still a need for more studies on the benefits of other conditions such as HIV/AIDS, liver disease, and weight loss. According to the FDA, Lipoic acid is safe and effective, and promising uses can be explored in future studies. 

Mechanism of Action

Lipoic acid/reduced dihydrolipoic acid as an antioxidant

The chemical reactivity of Lipoic acid is mainly conferred by its dithiolane ring. The oxidized (Lipoic acid) and reduced (reduced dihydrolipoic acid) forms create a potent redox couple that has a standard reduction potential of − 0.32 V. This makes reduced dihydrolipoic acid one of the most potent naturally occurring antioxidants. In fact, there is evidence that both Lipoic acid and reduced dihydrolipoic acid are capable of scavenging a variety of reactive oxygen species. Both Lipoic acid and reduced dihydrolipoic acid may scavenge hydroxyl radicals and hypochlorous acid, while Lipoic acid also terminates singlet oxygen. Neither species is active against hydrogen peroxide. Lipoic acid, and especially reduced dihydrolipoic acid, have the ability to prevent protein carbonyl formation by scavenging hypochlorite. Furthermore, reduced dihydrolipoic acid appears to regenerate other endogenous antioxidants (e.g. vitamins C and E) and has the salubrious property of neutralizing free radicals without itself becoming one in the process.[2]

Lipoic acid as a metal chelator

In addition to being direct reactive oxygen species scavengers, both Lipoic acid and reduced dihydrolipoic acid chelate redox-active metals in vitro and in vivo. The oxidized and reduced forms bind a number of metal ions, but with different properties depending on the metal chelated. In vitro studies show that Lipoic acid preferentially binds to Cu2+, Zn2+ and Pb2+, but cannot chelate Fe3+, while reduced dihydrolipoic acid forms complexes with Cu2+, Zn2+, Pb2+, Hg2+ and Fe3+. We provided in vitro evidence that reduced dihydrolipoic acid, but not Lipoic acid, strongly inhibited Cu(II)(histidine)2-mediated ascorbate oxidation in a concentration-dependent manner. These results were in agreement with a report showing that only reduced dihydrolipoic acid prevented Cu(II)-mediated oxidation of LDL in vitro. reduced dihydrolipoic acid-mediated chelation of iron and copper in the brain had a positive effect in the pathobiology of Alzheimer's disease by lowering free radical damage. Thus, a growing body of evidence suggests that reduced dihydrolipoic acid chelates transition metals in a redox-inactive manner, and in turn mitigates metal-catalyzed free radical reactions in conditions where they accumulate.

Whether Lipoic acid/reduced dihydrolipoic acid effectively chelates and removes transition metals in vivo is still to be fully elucidated. In this regard, Goralska et al. showed that treating lens epithelial cells with Lipoic acid significantly lowered the rate of iron uptake and the size of the intracellular labile iron pool. Feeding R-Lipoic acid to old rats for 2 weeks reversed the age-related increase in cerebral cortex iron. Importantly, feeding Lipoic acid did not affect either normal metal levels in young rats or lower iron status in old rats below that seen in young animals. Nor was Lipoic acid or reduced dihydrolipoic acid capable of removing iron from aconitase or copper from superoxide dismutase. These results imply, but do not yet prove, that Lipoic acid supplementation may modulate the labile pool of redox-active transition metals, without causing metal depletion.

Is Lipoic acid a direct-acting antioxidant?

Although strong in vitro evidence supports the role of the Lipoic acid/reduced dihydrolipoic acid couple as a potent antioxidant, it remains questionable whether they can scavenge free radicals effectively in vivo. Because Lipoic acid only transiently accumulates in vivo and is rapidly catabolized, it is difficult to envision how Lipoic acid could augment endogenous antioxidant capacity on a sustained basis. The antioxidant properties of Lipoic acid in vitro may be explained as follows: i) cell culture studies are often conducted with Lipoic acid concentrations that are several fold higher than what has been seen in plasma or tissues after an oral dose, and ii) Lipoic acid and reduced dihydrolipoic acid are not cleared from the culture media in a rate that replicates disposal in the body, where 98% of radiolabeled Lipoic acid is excreted in the urine within 24 h. Thus, typical cell culture conditions likely overestimate the direct antioxidant capacity of Lipoic acid via one-on-one interaction with free radicals. Alternatively, the ability of Lipoic acid to indirectly induce or maintain endogenous antioxidant levels even in times of oxidative or toxicological stress may be more relevant than a direct-acting antioxidant role, and the data to support this will now be discussed.

Lipoic acid as an inducer of endogenous antioxidants

There is growing evidence that Lipoic acid may act indirectly to maintain cellular antioxidant status by either inducing the uptake or enhancing the synthesis of endogenous low molecular weight antioxidants or antioxidant enzymes. For instance, reports show that Lipoic acid increases intracellular ascorbate levels. Even in rats, which synthesize ascorbate, Lipoic acid feeding increases hepatic ascorbate levels, which otherwise decline with age. Michels et al. extended this research to show that an age-related loss of sodium-dependent vitamin C transporter 1 (SLC23A1) was at least partly responsible for the decline in hepatic ascorbate. Feeding Lipoic acid to old rats may therefore induce ascorbate uptake from the exogenous milieu. Rat cardiomyocytes exhibit an age-related decline in ascorbate concentrations, but dietary R-Lipoic acid restored ascorbate levels and lowered the rate of oxidant production to the level seen in young rats. Moreover, Xu et al. observed that the reduction of dehydroascorbic acid to ascorbate in rat liver mitochondria was enhanced in the presence of Lipoic acid. These studies thus indicate that Lipoic acid may improve endogenous ascorbate levels indirectly by inducing uptake from the blood plasma.

In concert with improving ascorbate status, Lipoic acid markedly increases intracellular glutathione (GSH), an abundant natural thiol antioxidant and co-substrate for detoxification enzymes, in a variety of cell types and tissues. Packer et al. showed that Lipoic acid treatment enhanced GSH levels in human cell lines and primary cells, including T cells, erythrocytes, lymphocytes, and glial and neuroblastoma cells. These authors concluded that reduced dihydrolipoic acid reduced cystine to cysteine, which is the limiting substrate for GSH synthesis. [3]

Adverse Effects and Toxicity

Lipoic acid is considered a safe supplementation without any adverse effects. One study supports the safety of the drug, and an adult can take up to 2400 mg without experiencing any harmful adverse effects. High doses of Lipoic acid are not recommended as higher doses provide no additional benefits. The most common adverse effects reported with Lipoic acid are headache, heartburn, nausea, and vomiting. A 1996 Lipoic acid study on 6 rhesus monkeys showed that excess lethal doses in primates would cause hepatic necrosis. Researchers noted that 3 out of 6 monkeys that received 90 mg/kg to 100 mg/kg of intravenous Lipoic acid exhibited large necrotic areas in the muscles of their thighs, the liver, the heart, and the kidneys. This situation led the researchers to conclude that exceptionally high doses of IV Lipoic acid can produce the same symptoms that smaller doses prevent.

References

[1] Packer L, Cadenas E. Lipoic acid: energy metabolism and redox regulation of transcription and cell signaling. J Clin Biochem Nutr. 2011 Jan;48(1):26-32.

[2] Golbidi S, Badran M, Laher I. Diabetes and alpha lipoic Acid. Front Pharmacol. 2011;2:69.

[3] Pirlich M, Kiok K, Sandig G, Lochs H, Grune T. Alpha-lipoic acid prevents ethanol-induced protein oxidation in mouse hippocampal HT22 cells. Neurosci Lett. 2002 Aug 09;328(2):93-6.

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