Introduction

α-Lipoic Acid (ALA) is a medium-chain fatty acid biosynthesized by cleavage of linoleic acid. Its molecular formula is C8H14O2S2, and its molecular weight is 206.32556. It contains an octanoic acid bridged with two sulphurs, and its International Chemical Identifier, according to the International Union of Pure and Applied Chemistry, is AGBQKNBQESQNJDSSDOTTSWSA-N. ALA exists as two stereoisomers: R-(+)-ALA and S-(-)-ALA. In nature, R-(+)-ALA is encountered in plants such as spinach and broccoli, as well as in small animals' heart, liver, and kidneys, and represents a coenzyme of oxoglutarate dehydrogenase. In these, it delays and/or reduces tissue oxidation. Medical preparations contain a racemic mixture of both stereoisomers. Following drug administration, the R-(+) stereoisomer is more rapidly and completely absorbed than the S-(-) stereoisomer.

Benefits

α-Lipoic Acid, also known as thioctic acid, is a potent lipophilic antioxidant with the ability to scavenge free radicals. In experimental models, this antioxidant effect has been clearly shown to reduce lipid peroxidation, improve endoneurial blood flow and glucose uptake, correct deficits in neuropeptides, enhance the activity of endogenous protective superoxide dismutase and catalase, reduce ischemia–reperfusion injury, and prevent apoptosis[1]. In humans, ALA has been investigated since 1959 by both small single-blind and larger double-blind, randomized placebo-controlled clinical trials. ALA has been administered orally at doses between 600 and 1800 mg, as well as intravenously at 600 mg/d for 3 weeks, excluding weekends. The meta-analysis of intravenous investigations has shown that ALA is efficacious in ameliorating neuropathic symptoms (pain, burning, and numbness) and neuropathic deficits (ankle reflexes, pinprick, and touch–pressure sensation) with a number needed to treat (NNT) of 6.3 and excellent safety profile. Results with oral ALA have been less consistent. However, the most recent and largest trial showed improvement in neuropathic symptoms (especially lancinating and burning pain) and sensory deficits, though not in nerve conduction parameters. The trial lasted 5 weeks, and the 600 mg dose provided the optimal risk-benefit ratio. Based on this latter work, oral ALA appeared promising, but clearly, more experience and longer follow-up data were necessary.

Mechanism of action

Experimental evidence suggests that ALA restores glutathione levels, prevents lipid peroxidation, increases the activity of antioxidant enzymes (such as superoxide dismutase and catalase in peripheral nerves) and increases blood flow, glucose uptake, and metabolism in peripheral nerves along with nerve conduction velocity (NCV). Moreover, it corrects thecits of neuropeptides (such as Neuropeptide Y and substance P) in the spinal cord and suppresses the activation of NF-kB in peripheral nerves. It also exerts a neuroprotective action against reperfusion injury, promotes adenosine triphosphate activity, reduces excess lipid oxidation and ameliorates hyperalgesia[2].

ALA has been studied in other diabetic complications as well. In experimental diabetic retinopathy, it may reduce oxidative stress in retinal mitochondria and improve their metabolism. In this setting, there is some evidence that it may improve tissue oxygenation and manganese ion uptake in the retina. In humans, a clinical trial with ALA supplementation failed to demonstrate prevention of diabetic macular oedema. However, another study including diabetic subjects who had not yet developed retinopathy and who received ALA in combination with other antioxidants showed improvements in electroretinogram. In experimental diabetic nephropathy, ALA has been shown to reduce urinary albumin excretion rate and kidney oxidative damage with a protective action on mitochondria. Two small human trials showed a reduction of thrombomodulin and oxidative stress markers without consistent benefit in microalbuminuria. More recently, however, ALA plus pyridoxine supplementation significantly reduced microalbuminuria, advanced glycation end-products, and systolic blood pressure, with a concomitant increase in serum NO. Finally, ALA has also been investigated for erectile dysfunction. It has shown some beneficial effects in the corpus cavernosum relaxation of diabetic animal models. A recent 12-week open-label trial has shown that ALA treatment could improve erectile function along with the body-mass index, HbA1c and serum lipids.

Reference

1. N Papanas, E Maltezos. “α-Lipoic acid, diabetic neuropathy, and Nathan’s prophecy.” Angiology 63 2 (2012): 81–3.

2. Papanas N, Ziegler D. Efficacy of α-lipoic acid in diabetic neuropathy. Expert Opin Pharmacother. 2014; 15(18): 2721-2731.