Capsaicin, Curcumin, apignen, isoflavone, Lithium, TCI's and LLLT

[Moxsimux]

Let me say first that I'm a pre-mature balding male (Diffuse thinner). I'm already on some treatments but looking for the best possible topical. I'm doing a Biology degree and have a little background in chemistry but have yet to make any of my own topicals.

I have put together a list of personally what I think would be included in an excellent topical, which will be back by scientific articles.

Capsaicin, Isoflavone

Harada et el proved that the administration of capsaicin and isoflavone significantly increased hair follicles more then capsaicin alone and significantly more then placebo in patiets with AGA (Androgenic Alopecia). Capsaicin activates vallinoid receptor 1, which in turn activates calcitonin gene-related peptide, which has shown to increase IGF-1. Tang et el (2003) were able to prove that the individuals using a DHT inhibitor and had significant regrowth all had higher levels of IGF-1 in the scalp opposed to the subjects using DHT inhibitor who did not show growth, or those which showed loss.  It has been proven that IGF-1 plays a vital role in hair bulge stem cell proliferation and differentiation (Werger 2005, Su 1999). Rasberry Ketone contains properties that are quite similar to capsaicin and are one of the main ingredients in Virile Mane, a product with good reviews for hair regrowth.
 
So in combination capsaicin and isoflavone seem to be an excellent addition to any topical.

Curcmin, Apignen

It has been shown that Transforming Growth Factor Beta-1 (TGFB-1) plays a crucial role in catagen induction when in the presence of androgens (Huh, 2009, INUI 2002). Curcumin is a known inhibitor of TGFB-1. It is also shown that Apignen decreases levels of TGFB-1 and also increases human epidermal keratinocytes and human dermal papilla cells. It is an anti-oxidant, anti-inflammatory and has anti-tumor properties.

In conclusion, these products seem also effective, but lack the studies of actually being used on AGA patients. (none that I could directly find yet)


The next few items obviously can't be used in custom topicals made via companies because they require a prescription and are used for different medical conditions. Use at own risk

Lithium and (2'Z,3'E)-6-bromoindirubin-3'-oxime (BIO)

Already on this board they have spoke about Lithium and everything was on par with my research.  Lithium and BIO are GSK-3 inhibitors which in turn inhibits the Wnt signal pathway (Yamauchi,  2009). The Wnt signalling pathway has been shown to be a important role in hair follicle proliferation and differentiation (Ouji 2008). Clearly more research needs to be done on this area as it is undetermined with wnt pathways are activated by inhibiting GSK-3.

I have no idea where one could retrieve the BIO, as I am not familiar with it at all.


TCI's

TCI's are topical calcineurins inhibitors. Bascially the NFAT-1 - calceineurin pathway plays a major role in keeping hairs in quiescenence and not dividing and proliferating into more hair cells. Calcerineurins inhibitors stop this pathway and activate growth of new hair cells potentially. One of the most common side effects of treatment with cyclosporin A  is hypertrichosis. Horsley et el  (2008) showed that calcineurin activity is associated with hair keratinocyte differentiation in vivo, affecting nuclear factor of activated T cells (NFAT1) activity in these cells. As stem cells become activated during hair growth, NFATc1 is downregulated, relieving CDK4 repression and activating proliferation. When calcineurin/NFATc1 signaling is suppressed, pharmacologically stem cells are activated prematurely resulting in massive follicular growth. (Gafter-Gvili 2003).

Again TCI's are used for completley different medical purposes. Do not attempt this at home. Just an idea of how to regrow some hair with topicals.

I also have a new theory on Heat Schock Proteins (HSPs) and hair regrowth. I will explain this in more detail later.

So overall I was wondering If this could possibly be made. Especially the first 4 or 5  substances with stability?



Gafter-Gvili A, Sredni B, Gal R, Gafter U, and Kalechman Y. Cyclosporin A-induced hair growth in mice is associated with inhibition of calcineurin-dependent activation of NFAT in follicular keratinocytes  Am J Physiol Cell Physiol 284: C1593-C1603, 2003;
 
Harada N, Okajima K, Arai M, Kurihara H, Nakagata N. Administration of capsaicin and isoflavone promotes hair growth by increasing insulin-like growth factor-I production in mice and in humans with alopecia. Journal of Growth Hormone & IGF Research. Volume 17, Issue 5, October 2007, Pages 408-415

Horsley V., Aliprantis AO, Polak L, Glimcher L. and Fuchs E. NFATc1 balances quiescence and proliferation of skin stem cells Cell. 2008 January 25; 132(2): 299–310.

Huh S, Lee J, Jung E, Kim SC, Kang JI, Lee J, Kim YW, Sung YK, Kang HK, Park D.
A cell-based system for screening hair growth-promoting agents. Arch Dermatol Res. 2009 Mar 11.

Ouji Y, Yoshikawa M, Moriya K, Nishiofuku M, Matsuda R, Ishizaka S. Wnt-10b, uniquely among Wnts, promotes epithelial differentiation and shaft growth. Biochemical and Biophysical research communications. 2008 Mar 7;367(2):299-304

Tang L, Bernardo O, Bolduc C, Lui H, Madani S, and Shapiro J.The expression of insulin-like growth factor 1 in follicular dermal papillae correlates with therapeutic efficacy of finasteride in androgenetic alopecia. Journal of the American Academy of Dermatology. . 2003 Aug;49(2):229-33.

Weger N, and Schlake T. Igf-I signalling controls the hair growth cycle and the differentiation of hair shafts. The Journal of Investigative Dermatology. 2005 Nov;125(5):873-82


Sorry about the lazy references, let me know if I forgot any.

[DrYechiel]

Hello Moxsimux,

Thank you for your posting. You actually put together a mini review article and I am quite impressed with your effort. To give you a detailed answer, I will need some time but I will give an initial response which is aimed to put some of the feedback cycles which you mentioned into a real life arena where neat laboratory results are more difficult to obtain.

Let me start with an example which is not directly related to the examples you brought up. As a biology student you are probably aware that cells are more then simply bags full of chemicals. They also have ultra-structures (see later for relevancy). You are also probably aware of one of the mysteries which were popularly discussed a few decades ago and is still a mystery, “The Oxygen Paradox”. When people are under conditions of hypoxia or under prolonged myocardial ischemia (due to reduced oxygen supply to the heart muscle) and are treated by high doses of oxygen, the treatment will many times result in heart failure. The oxygen paradox also happens in re-perfused ischemic heart cells which indicates that the initial worsening effect of oxygen flow into a network of constricted blood vessels (probably from hyperventilation due to high carbon dioxide) is not sufficient to explain why it also happens in cell cultures or in experiments in isolated heart systems. It is suggested that since many cardiac cells may have died, the extra mechanical load to the heart cells when they function normally because of the increase in oxygen is too much for them and they die. It is true that many of the reasons which were suggested to explain the phenomenon have merit but they are not sufficient to fully explain the oxygen paradox. I have suggested in an experiment (which I unfortunately did not publish) that there is one more reason to consider and it is the state of injury that most or all the heart cells endure during hypoxia rather than the death of some of the cells (though death of some of the cells is certainly an important factor in weakening the performance of the heart). When heart cells are injured and are pushed to act at full output while still injured by reperfusion of oxygen, they die. It is that simple. Life needs strong physical platforms to support the performance of life-giving biochemical cycles. When a physical platform is injured, the increased activity at the biochemical level may cause further damage, though it may appear in a short-term observation that things look better. In the case of hypoxia, it may be better to infuse minimum essential oxygen for a period to allow as many of the cells as possible to recover and gradually increase the oxygen in conjunction with such recovery. I found that gradually re-perfused cells had a better chance of recovery (again, I am sorry I did not publish the experiment).

I believe that this may be why minoxidil causes hairloss when people start it and when they withdraw from it. It helps the chemical mechanism (biochemical cycles) of hair growth but it is not helpful (and maybe damaging) to the whatever is left of the physical platform (the ultra-structures which support and regulate chemical reactions) on which hair-growth biochemistry operates. In the case of hair follicles, the big question is whether the damage to the “physical platform” is reversible or not. If the damage is part of the aging process (and some organs age faster than others), then the answer will be to focus on real anti-aging treatments. If the injury is not age-related and the cells are still alive (though barely), the answer is not to push them hard chemically but treat them slowly to physical recovery first. When they recover, all the chemical mechanistic arguments may be applied but will most likely be un-necessary because the hair will grow, even with less than perfect chemical mechanisms and besides, chemical mechanisms may also get perfected when the “physical platforms” are recovered. To find more on what these” platforms” may be, you can read about my theory of aging in the Journal of Topical Formulations. I have presented my theory of “bio-structural loss” theory of aging in some of my presentations and one you may want to read is "Anti-Aging Actives in Nano-Cosmeceuticals: The Bio-Structural Theory of Aging" which is linked to by http://www.topical-formulations.com/.

This is also why we developed the concept of dynamic synergy and are offering a 6-month regimen which takes the scalp into a higher level of performance one step at a time while changing the scalp environment. The jump-steps in the regimen offer increasing “chemical exercise” where the scalp is exposed to changing conditions which adds a gradually increasing challenge to the scalp. The dynamic synergy concept is also discussed in the Journal of Topical Formulations, at http://www.topical-formulations.com/topical/200807/dynamic-synergy.htm. Many active ingredients including many from the list you posted are in the products which comprise the regimen and also include anti-aging ingredients which are most compatible with structural integrity issues in scalp.

I will address more directly to your “mechanistic” suggestion in a few days. You are welcome to comment back even before Part II of my reply is posted.

Thank you for your posting.

[Moxsimux]

Dr. Yechiel,

I am very impressed with the thoroughness and timley response. It has been months since the last post on this board. Is there a reason you stopped this journal, was there a lack of interest?

Also, that was an excellent anology the hairloss paradox. It is barely understood but we are slowly figuring out some of the mechanisms dealing with the complexity of the hair organ. I will have to do some research into the dyanmic synergy concept. It seems like you have put alot of long hours into the research.

As well I have a theory of Heat Shock Proteins which I will give a quick synopsis of and maybe you could tell me what you think;

Lately I have been reading about diet, baldness and more recently insulin-resistance in these individuals. Gonzalez et el. proved that young androgenic alopecia individuals do have an signifigant correlation to resistance to insulin. Normally this is a trait you would view in type 2 diabetics. Which struck me as odd.

What does this tell us? perhaps balding and insulin-resistance share some pathways. Low expression of Heat shock proteins (HSP) are found in individuals who are highly insulin resistant. There has not been alot of work done on this area but Aldy et el has found expression of the HSP only in anagen phase hairs. There were no HSPs found in telogen or catagen hairs. So we can induce that insulin resitant men are prone to balding, and it has been studied that expression of HSP's is low in AGA males. (Bahta, 2008)

In a pilot study for treatments of Androgenic Alopecia with cell cultured medium, Lindenbaum et el. (2003) where able to grow hair on par with minoxidil with what being the main ingredient? Insulin. Telling to say the least. Also There have been a few studies of the effectiveness of Low Level Laser Therapy (LLLT) on Heat Shock Proteins. (Soule, 2001)

Another benificial thing to having raised levels of HSP is that it inhibits GSK-3. GSk-3 is a protein that inihibits the Wnt signalling pathway. You want Wnt signalling for hair regrowth. Also I think Histogen is focusing on the upregulation of Wnt.

I lost my references ATM, but will get back to you on them. I'll let you finish approaching the first question.

[HelenJames]

The similar subject was already observed somewhere at this thread