R-Lipoic Acid is the eutomer of Lipoic Acid

July 1, 2013 Science Blog By

Question: Is there really any solid evidence that R-(+)-lipoic acid (RLA, RALA or dextro-lipoic acid) is any better for humans than racemic alpha (+/-)-Lipoic acid (rac-LA) or the unnatural S-(-)-lipoic acid (SLA), or is it just a hypothesis?

Wouldn’t you expect that all forms of lipoic acid share similar antioxidant effects due to the lack of stereospecificity in the reaction with free radicals?

David Carlson’s answer:

First, the latest research indicates that lipoic acid is not primarily a radical scavenger, but is rather a cytoprotective (protecting cells from damage expected to occur) agent that improves the cellular antioxidant status, possibly and paradoxically via a pro-oxidant induction of phase two detoxification gene products.

Although the biological similarities and differences between R-lipoic acid (RLA), S-Lipoic acid (SLA) and racemic Alpha-Lipoic acid (racALA) are not fully characterized, the evidence is stacking up that RLA is in general, the eutomer (the physiologically and therapeutically preferred enantiomer) so the science has advanced beyond “speculation or hypothesis” (see http://www.geronova.com/included/docs/contents_book_chapter_10.pdf ).

We are currently working on a paper about this. After a comprehensive literature search we compiled every known experiment evaluating some aspect of Lipoic acid stereochemistry (see:http://www.geronova.com/included/docs/ABC.pdf). We are still tallying the results but so far in~80% of the cases R-(+)-lipoic acid was preferred to SLA or racLA (50% RLA:50% SLA) at the same concentration and under the same conditions.

Please review the refs 1-7 on the SLA page on the website http://www.geronova.com/products/in_house_research/lipoic_acids/s-lipoic_acid
and refs 20-28 from our pharmacokinetics (PK) paper http://www.thorne.com/altmedrev/.fulltext/12/4/343.pdf.

The situation is complicated by the fact that some reactions are stereoselective and others are not, and SLA can act either neutrally, contribute to the effects of RLA, act as isomeric ballast (along for the ride but not inhibiting the effects of RLA), or act as a competitive inhibitor of RLA. The examples of competitive inhibition become the limiting criteria in vivo.

Due to the significant difference between the pharmacokinetics of RLA, SLA, and racLA http://www.geronova.com/included/docs/Comparison_PK_poster.pdf it is clear that even when the reactions are non-stereoselective, you get more “bang for the buck” with RLA as NaRLA (encapsulated or as a per oral solution). Interestingly, two of the prime mediators of the therapeutic effects of Lipoic acid  are two signaling proteins; AMPK and Nrf2. Both have a strong stereoselective preference for RLA over SLA. All of the ability of lipoic acid to activate Nrf2 is found in the R-enantiomer or lipoic acid R-form.

That means it is stereospecific (100% RLA and 0% SLA). Nrf2 activation is one of the primary beneficial mechanisms of action for the nutritional and therapeutic effects of Lipoic acid, providing strong evidence that it is the form that should be consumed. With AMPK there is preliminary evidence that this critical “energy-sensing” protein is stereoselective for RLA but not stereospecific like Nrf2.

I have been motivated in my work by the simple but profound concept that only R-Lipoic acid has been used by nature for at least a billion years whereas SLA and racLA have only been around since 1952. If you were a gambler, you would say the odds favor some significant and possibly as yet unknown in vivo difference between the various forms of LA.

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