Since this question is flooding my email and PM folder, I will post my brief email-reply here:
Hello ChemicalBrother,
Actually I am on my way on vacation so I don´t have much time but I will try to give a short answer.
I guess you are referring to the post by @science on HLH which I quote here:
<<"GLA induces pgh1 synthesis , and pgh1 is a potent crth2 antagonist.. (so yes not good for hairloss),
it gives exactly the opposite effects of CRTH2 antagonist like OC."
anon.
GLA is one of the main ingredients in this product.
2. Pro-B3.. check the absorption of that dermally the numbers are beginning to add up on that one.
which is another main ingredient. >>
Let me first answer to the second point.
In this publication the effectiveness of Procyanidine-B3 for hair growth promotion was shown in vitro but also IN VIVO and they used an inferior vehicle to ours:
http://www.ncbi.nlm.nih.gov/pubmed/12473061
If he wants you to “check” something about the dermal absorption why is he not showing what he found out by his “check”? Procyanidin-B3 got absorbed in the above study with an inferior vehicle and it worked so it will work even better with our vehicle.
I hope I understood his sentence right, it appears strange verbalized to me.
Whoever has this concern if not he himself, that person may not be aware of the transfollicular route for skin absorption where larger molecules can be transported into the skin, which are too large for penetration of the skin in between the hair follicles. In addition, our microencapsulating vehicle helps with the transport of large molecules. For example, liposomes have been shown to increase skin penetration of cyclosporin A (but we don´t use liposomes).
I will now answer to the first point.
This point is a valid point, although he made a mistake in his sentence; Prostaglandin H1 (PGH1) is a CRTH2 agonist and not an antagonist. You can read about this issue here:
http://www.plosone.org/article/info%3Ad ... ne.0033329
Gamma Linolenic Acid is special; although it is an omega-6 unsaturated fatty acid it acts as an anti-inflammatory most of the time. You can read this up in many publications, I will mention just a few here:
http://shikai.com/publications/GLA-A%20 ... yAgent.pdf
http://www.mendeley.com/research/gamma- ... atty-acid/
http://rd.springer.com/article/10.1007/BF01986575
http://www.ncbi.nlm.nih.gov/pubmed/10617998
Note the inhibition of INF-gamma, a potent hair loss inducer. Note also the inhibition of some IL-… which are also known as hair loss inducers. So besides its 5-AR inhibition activity, GLA also acts as an anti-inflammatory most of the time.
If the major action of GLA would be the activation of CRTH2 via PGH1 its net action would be pro-inflammatory and not anti-inflammatory. But GLA has also other metabolites like PGE1, PGA1 and to 15-hydroxy-eicosa-trienoic acid (15-HETre). Prostaglandin H1 itself has metabolites which don´t activate CRTH2, quote from the article (when I say “the article in the following I always mean this one
http://www.plosone.org/article/info%3Ad ... ne.0033329):
“The PGH1 precursor DGLA and the other PGH1 metabolites did not display such effect.”
DGLA = dihomo-γ-linolenic acid (DGLA)
GLA gets metabolized to DGLA. DGLA gets metabolized to 15-hydroxy-eicosa-trienoic acid (15-HETre) which acts as an anti-inflammatory. A part of DGLA is metabolized to the intermediate PGH1, as said in the article, but it is just an intermediate, it gets metabolized further to the anti-inflammatory 1-series PGs PGA1 and PGE1. I don´t know the half-life of Prostaglandin H1 but importantly the net effect of GLA is usually anti-inflammatory. The metabolites of PGH1 again don´t activate CRTH2, see quote above.
PGF 2alpha activates CRTH2, too:
http://www.ncbi.nlm.nih.gov/pubmed?term ... 20receptor
However, PGF 2alpha is known as a hair growth stimulator:
http://www.ncbi.nlm.nih.gov/pubmed/15854125
In the end all theory can give us just an idea but nature is very complex and in the end the experiment has to decide. The experiment says that the major action of GLA is usually anti-inflammatory and not pro-inflammatory; the reason for this may be that PGH1 is just one of many intermediates of GLA but that is speculative. The action may also be context dependent.
Quote:
“Compared to PGD2, PGH1 acted as full agonist only in DMR assays on recombinant cells, but in all other functional readouts including those in primary eosinophils and Th2 cells, respectively, PGH1 behaved as a partial agonist. These data imply that PGH1 intrinsic activity may depend on both the assay system under study and the receptor density which is likely to be lower in cells expressing the receptor in its native environment. Nonetheless, these data clearly suggest that both eosinophils and Th2 cells can be activated by PGH1 in the absence of generation of endogenous PGD2.“
PGH1 serves as intracellular substrate for the PG synthases which produce the anti-inflammatory PGs PGE1 and PGA1 from PGH1. In order to act as a CRTH2 agonist the PGH1 must be released into the extracellular space.
Quote:
“Although the exact physiological concentrations of H prostaglandins in the extracellular space at the site of inflammation may be difficult to determine, there is evidence that H prostaglandins do not only serve as intracellular substrates for PG synthases, but may also be secreted from cells in an untransformed manner [73]–[78]. „
If this happens to a problematic amount in our scalp is connected with a big “may/if”. As I said, it likely depends on the context, IL-1beta may trigger such a release. It seems to me that GLA acts in skin predominantly as an anti-inflammatory but may be problematic in the lung of asthma patients.
Gamma Linolenic Acid has been used by revivogen for a long time, I guess they would have noticed by now if their product would cause hair loss.
I want to mention a publication which is even newer than the one on PGH1 and CRTH2; the authors investigated the delivery of gamma linolenic acid (as part of an extract) into the skin and they suggest the application for the treatment of androgenetic alopecia.
In the end the results count. We know our product works from our own experience and more and more positive reports are coming in and no negative reports appeared so far.
Although alternatives for GLA are possible, we don´t see the need to change the formula since it works so well. Who knows if it will still work that well if we replace GLA.
I hope these lines were helpful.
I wish you a Happy New Year!
Best Regards,
Synthese Advisor
