'Inhibition of Inflammatory Gene Expression in Keratinocytes Using a ...'

Chronic inflammation of the hair follicle (HF) is considered a contributing factor in the pathogenesis of androgenetic alopecia (AGA). Previously, we clinically tested liposterolic extract of Serenoa repens (LSESr) and its glycoside, beta-sitosterol, in subjects with AGA and showed a highly positive response to treatment. In this study, we sought to determine whether blockade of inflammation using a composition containing LSESr as well as two anti-inflammatory agents (carnitine and thioctic acid) could alter the expression of molecular markers of inflammation in a well-established in vitro system. Using a well-validated assay representative of HF keratinocytes, specifically, stimulation of cultured human keratinocyte cells in vitro, we measured changes in gene expression of a spectrum of well-known inflammatory markers. Lipopolysaccharide (LPS) provided an inflammatory stimulus. In particular, we found that the composition effectively suppressed LPS-activated gene expression of chemokines, including CCL17, CXCL6 and LTB(4) associated with pathways involved in inflammation and apoptosis. Our data support the hypothesis that the test compound exhibits anti-inflammatory characteristics in a well-established in vitro assay representing HF keratinocyte gene expression. These findings suggest that 5-alpha reductase inhibitors combined with blockade of inflammatory processes could represent a novel two-pronged approach in the treatment of AGA with improved efficacy over current modalities.

Source:
http://www.ncbi.nlm.nih.gov/pubmed/19692448?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Here's the fully study:

http://ecam.oxfordjournals.org/cgi/content/full/nep102v1

Also for those that do not know, Thioctic Acid is the same as alpha lipoic acid.

I posted a massive thread on Hairloss talk.com about how combining anti-inflammatories both topially and internally along with Finasteride would result in a more effective treatment for Androgenetic Alopecia. It's clear that inflammation plays a key role in AGA, but whether it is a side-effect or a cause of the degradation of the follicle is unknown to me..

Maybe you could clear this up for me CS, I've asked about scalp inflammation twice to you and you talk about external factors like shampoo etc. or about diet. What do you believe is the corellation between DHT and inflammation, where in the process does this occur?. I realise that you aren't exactly and extreme premature AGA sufferer do you might not have felt the "itch" like some of the younger guys have. But, I used to always check with the youngest guys introducing themselves on Hairloss Talk.com and they always seemed to have aggressive inflammation as opposed to the older guys who have a lot less and in some cases don't feel any at all. Though I believe inflammation to always be there, microinflammation would not be felt but would be doing damage either way. In other words the younger you get the worse inflammation is and since many older men who suffer AGA might not expierience it they might overlook it. My inflammation is extreme at times where it is hard to get asleep. Don't get me wrong though it's not SD, I just have a high deposition to hair loss. I was thinking that maybe some natural anti-inflammatories might aid this, but I believe these won't be enough, because you'd have to tackle the root of the problem which is DHT. Anyways, if that made any sense, the main aspect I try to understand is if you completely rid your scalp of inflammation would this halt hair loss, or would hair loss still occur from DHT choking the follicle?. Is it the cause of death or just a side effect?

Here's some articles on the subject:
http://www.hairloss-research.org/february1.html
http://www.androgeneticalopecia.com/hair-loss-biology/hair-loss-inflammation-baldness.shtml
http://www.hairlosshelp.com/forums/messageview.cfm?catid=10&threadid=62444
http://searchwarp.com/swa23645.htm

Decro435 - In the late 90's when I was heavy on natural DHT blockers such as Saw Palmetto, Pygeum, etc., I suffered a lot of scalp itch, no doubt about it.

I do not recall this itch occurring before using the treatments however.

My regimen is primarily based on counteracting inflammation, followed by reducing DHT sensitivity, and finally by inhibiting excess DHT.

There are lots of questions on what is the exact cause and so far it is not fully understood. We know for instance that DHT signals DKK-1, a highly negative gene that is upregulated in balding dermal papilla. It's also implicated in reducing the activity of osteoblasts which are responsible for building bone. DKK-1 inhibits Wnt signaling which is essential for hair growth. It is possible that this can be counteracted by controlling levels of lipoprotein(a) or possibly by decreasing the upstream JNK/c-Jun signaling, which involves optimizing vitamin D levels (70 to 80 ng/mL).

(DHT) stimulates synthesis of transforming growth factor-Beta2 in dermal papilla cells, that is where curcumin comes in.

Various factors, including TGF-beta increase expression of serine proteinase enzymes such as MMP-9 which are responsible for follicle miniaturization, this is counteracted by Ecklonia Cava. Normally, Protease nexin-1, a serine protease inhibitor, which normally controls the over expression of MMP-9 is stymied by DHT (in balding scalps only).

There are other ways to reduce matrix metalloproteinase-9 and keep in mind that it is an inflammatory enzyme present in atherosclerotic lesions or plaque. So besides Ecklonia Cava there is Omega-3 fatty acids. Krill oil is a highly efficient form of EPA/DHA and lowers triglycerides significantly.

Some unanswered questions is how impactful are Malassezia yeasts, fungus, mites (demodex) and bacteria involved in the pathogenesis of AGA? Just one study shows there is a higher Malassezia count during shedding, and other lipase enzyme producing parasites emit this to break down triglycerides in the sebum which end up liberating an inflammation cascade of cytokines, AA, LOX, MMP's, etc. We know that certain antibiotics inhibit MMPs, such as doxycycline (I use Ecklonia Cava instead of this).

The population of these lipid subsisting organisms is hinged on androgen production since these are what stimulate how much sebum is produced. The more sebum, the greater the population of these organisms, the greater the inflammatory potential. Phospholipase A2 is a lipase enzyme that is secreted by these organisms to liberate arachadonic acid from the triglycerides in the sebum. This unleashes the inflammatory cascade.

Then there is bacterial folliculitus and its variants which cause fibrosis (scarring).

A lot of the "bad" proteins and enzymes mentioned are not always detrimental and serve many important and protective roles in the body. MMP's, TGF-beta are absolutely critical for good health and even hair, it depends on the a series of complex interactions in the body. I believe the key here is proper regulation of these substances.

Finally, there is a relationship between neurotrophins and hair cycling (neurogenic inflammation). This is highly complex, but involves stress and can be help counteracted by the Resveratrol/Curcumin by blocking the Cb1 receptor which regulates the endocannabinoid pathway.

Interesting study. And another one that mentions Serenoa repens aka Saw Palmetto as a viable treatment (along with ALC and ALA).

Thanks for that very informative answer Casutic!