Baldness Cure: Low Dose Naltrexone?

Naltrexone can be used to block opioids and provide the basis for treatment for drug abuse, but in low doses (LDN) it provides a paradoxical increase in natural endorphins that reverses inflammation and provides an effective treatment for autoimmune diseases, e.g. MS.

Receptors
A recent anonymous post brought the role of cannabinoid and opioid receptors in baldness to my attention. The relationship between these receptors, inflammation and autoimmunity is very complex. The heat and cold sensors, which also bind capsaicin and menthol, appear to be mediated by endorphins. Acupuncture also seems to function by similar mechanisms and is inhibited by high dose Naltrexone.

Low Dose Naltrexone
A side effect of high dose Naltrexone (e.g. 50 mg/d) is hair loss. Low dose Naltrexone (e.g. 1 mg/day, taken at night) appears to stimulate hair production and it may reverse the effects of Finasteride, since LDN improves libido.

Endorphin-Suppressed Inflammation
I would expect hair loss to be prevented/reversed by topical treatments that block inflammation and autoimmune attack on hair follicles. Curcumin, from turmeric, blocks NFkB and appears to help hair loss. Capsaicin can block inflammation via endorphin production and also helps hair loss. I would also expect that topical menthol and castor oil would reduce hair loss.

Anti-Inflammatory Diet
The anti-inflammatory diet that I recommend, may not be sufficient to block hair loss, but it may provide a good foundation for other anti-inflammatory treatments. In fact, other topical treatments may not be effective unless chronic, diet-based inflammation is eliminated. It may also be important to reduce oxidative stress by optimizing glutathione and vitamin C.

I would appreciate comments by others who may have experience with LDN and balding.

Prostate, Prostatitis, Cancer, Causes and Cures

Prostate problems are pervasive, and progressive in the U.S. -- approximately a quarter of a million prostate cancers are diagnosed each year. Chronic inflammation due to age or diet enhances prostatitis and cancer.

Prostate Surrounds Male Urethra

The prostate is a sexual organ. It responds to sexual stimuli, both physical and hormonal, and as a consequence is vulnerable to the same hazards: infection, inflammation, cycles of elaboration and cancer. The prostate straddles the male urethra and inflammatory swelling of the prostrate can strangle the flow of urine from the bladder. The prostate contributes part of the seminal fluid and backward flow of bacteria from the urethra into the prostate can be a source of infection.

Prostate Cells Require Testosterone for Growth

The prostate tissue responds to testosterone. The ebb and flow of testosterone, associated with sexual activity, results in increased production of prostate fluid containing proteins and other components that enhance performance of sperm in the female reproductive tract. The bottom line here is that prostate tissue and derived prostate cancer, responds to testosterone. For this reason, prostate cancer treatment has been based on blocking testosterone stimulation by removal of sources of testosterone and blocking testosterone receptors.

Testosterone Starvation Is Prostate Cancer Treatment

Testosterone, estrogen and vitamin D receptors are all cytoplasmic and the hormone/receptor complexes act as transcription factors to alter nuclear gene expression. It would be expected that prostate cancer, as well as breast, cervical, ovarian, testicular, etc. will respond in a complex manner to steroid hormones, including androgens, estrogens and vitamin D.

Cancer Requires NF-kB Activation

The common biochemistry supporting all cancers is inflammation that is required for proliferation in tissue. Central to inflammation is the transcription factor NF-kB. Inhibitors that block the activation of NF-kB also stop cancer. Most of these blockers are effective against cancer cells grown in culture flasks, because the inhibitors are taken directly into the cells and make contact with NF-kB (or stabilize the NF-kB inhibitor IkB.) Curcumin from turmeric, is one of the most potent inhibitors of NF-kB activation. It is very effective in cultures, but is only modestly effective against inflammation when eaten.

It is difficult to treat secretory tissues, such as prostate, breast, uterus, etc., because much of the tissue is separated from the blood circulation. Thus, infections in these tissues are harder to treat with antibiotics.

Prostatitis Results from Urinary Infections

The prostate is prone to chronic infections. Thus, urinary tract infections (UTIs) can lead to prostate infections (prostatitis). These chronic infections can contribute to chronic systemic inflammation. One symptom of chronic inflammation is depression (treated with SSRIs, antidepressants) another symptom is premature ejaculation (also treated with SSRIs.) Prostatitis-based inflammation can also set the stage for cancer.

Transglutaminase Autoantigen

Autoimmune diseases are also associated with chronic inflammation. One of the common autoantigens in autoimmune disease is tissue transglutaminase (tTG). Celiac is a classic example of the involvement of tTG, since tTG acts on the glutamine amino acids of gluten and converts them into glutamic acid residues. In the process tTG becomes covalently attached to the gluten. The strong heparin binding domains of tTG also facilitate its uptake and processing as an immunogen under inflammatory conditions and result in antibody production to both tTG and gluten. Anti-tTG antibodies and inflammation can also lead to attack on other tissues, such as the thyroid and skin, leading to a variety of celiac-associated autoimmune conditions.

The prostate produces its own transglutaminase. I think it is likely that prostatitis in some cases progresses to an autoimmune disease and prostate transglutaminase is a likely candidate for one of the autoantigens involved. This also predicts an association with celiac and a requirement for chronic systemic infection with a likely elevation of C-reactive protein and inflammatory cytokines (IL-1, IL-6, TNF). Deficiency of vitamin D and omega-3 fatty acids are probably major contributors. Increased risk attributed to consumption of a high fat diet and meat, is probably actually due to inflammation from a high carbohydrate diet and high omega-6 vegetable oils (or perhaps corn-fed meat.)

Protect Prostate with Anti-Inflammatory Diet

Prostate problems are frequently assumed to be a natural result of advancing age, but they are actually symptoms of mismanaged chronic inflammation. Men should not just stand and wait for prostate problems.

Avoidance and treatment of prostate problems seems to be an obvious application for an anti-inflammatory diet and lifestyle.

Extreme Flu Remedies

Experimental Therapies for ARDS, Cytokine Storms

Do not do this at home. There are doctors and hospitals. Use them.

....But, if a doctor emailed me pleading for any ideas that I had to save a bunch of patients suffering from acute respiratory distress syndrome (ARDS) from Tamiflu-resistant H1N1, my first response would be to suggest therapies designed for ARDS from other origins, e.g. burns, septicemia, etc.

Cytokine Storms Are Out of Control
When too much tissue is injured, the local, molecular communication that normally occurs just between cells, spills into the blood stream and becomes potentially lethal. That is what happens in anaphylactic shock. It is also what happens in cytokine storms, where inflammatory cytokines that are normally short-lived and processed locally to progress into recovery, erupt into the blood stream and impact distant organs.

Major disruption of body function by aggressive blood infections or burns over most of the body, will be lethal without heroic medical interventions. These are injuries beyond the evolved adaptations of mammals.  Until recently there were no survivors.

Influenza has been around for a long time. Humans, other mammals and birds get the flu and get over it. Many body cells become infected, antibodies specific to the virus are produced within about a week, the infected cells are killed, the virus is digested and life goes on.

People die from the flu, because an opportunistic pathogen causes a lethal secondary infection, or the body over-reacts and damages itself in attempts to attack its own infected cells. This is a cytokine storm.

Silence the Storms
Cytokine storms can be weathered by blocking the signaling system. Cytokines are just small proteins that are complementary in shape to corresponding protein receptors that penetrate through the surface membranes of cells throughout the body. Binding of cytokine to receptor changes the shape of the receptor and transmits a signal into the cytoplasm of the receptive cell. This turns on aggressive behavior of immune cells and triggers more inflammatory signaling in other cells. This causes fever, malaise, etc.

...But, I was the one the doctor is pleading with to save the people. And I know that there is more to cytokine signaling than just cytokines and receptors. There are also heparan sulfate proteoglycans (HSPGs). Cytokines are not supposed to be broadcast throughout the body. Cytokines function in the space between cells, the extracellular matrix. Polysaccharides attached to membrane proteins, HSPGs, are secreted at one end of the cells, sweep across the surface and are taken back up at the other end. Cytokines have heparan-binding domains and so they stick to the heparan and are swept along. Cytokines can move from one cell to another as the sweeping HSPGs of adjacent cells come in contact.

HSPGs Mediate Cytokine Signaling
The critical point here is that cytokines bind to their receptors with the heparan between -- the cytokine and receptor are like two halves of a bun and the hot dog is the heparan. In fact the heparan bridges two cytokine/receptor complexes to make an active, signaling pentamer.

Heparin Can Block Cytokine Signaling
Heparin is a fragment of heparan sulfate produced by enzymatic degradation of HSPG. Commercial heparin, used to block blood clotting, is obtained from the mast cells of lungs and intestines of hogs and cattle. The mast cells release heparin and histamine in response to parasites or pollen. Since heparin is a short version of heparan sulfate, it can block the formation of active cytokine/receptor complexes.

Heparin is used in a mist to treat the lungs of burn patients. It is also injected into some infertility patients to suppress inflammation that is inhibiting implantation and gestation. It is also effective in treatment of autoimmune inflammation in Crohn’s disease. I think it should be tested as a therapy for H1N1 cytokine storms. It may be useful in nebulizing mists and oral treatment of intestines.

Berberine Binds to HSPG
Berberine is a phytochemical from Barberry traditionally used in the treatment of intestinal infections and arthritis. It also binds to heparan sulfate to form fluorescent complexes visible in microscopy. Berberine-treated mast cells glow brightly. Heparan sulfate can also be detected in Alzheimer’s plaque, atherosclerotic plaque and prion complexes. Because berberine binds to heparan sulfate, it should also disrupt cytokine signaling. It has been used successfully in treatment of septicemic ARDS.

Curcumin Blocks NFkB
One of the most potent chemicals that blocks inflammatory signaling via the inflammatory transcription factor, NFkB, is curcumin. Curcumin is a major component of the spice turmeric. Oral curcumin can be enhanced by co-administration of black pepper, because the piperine in pepper inhibits intestinal inactivation.

Anti-Inflammatory Diet
Of course, I would also recommend vigorous implementation of an anti-inflammatory diet and lifestyle to support any medical treatment.

There Is More Than Antioxidants

Every time a plant product has an impact on a disease it seems to be attributed to its antioxidant activity. Plant products are active, because they bind to proteins. They bind to lots of different proteins.

Krill oil is a good example. The anti-inflammatory activity of krill oil is due to its omega-3 oil (DHA and EPA) content, but krill oil is more potent than expected. Krill oil also contains a terpene, astaxanthene, that is probably derived from its algae diet. Astaxanthene is labeled as an anti-oxidant, but that is much too easy.

Astaxanthene consists of two flat, hydrophobic paddles, connected by a flexible, hydrophobic chain. Those paddles are important, because of their inability to hydrogen bond with water, i.e. hydrophobicity, and therefore their propensity to get stuck in contact with other hydrophobic surfaces. The list of candidate hydrophobic surfaces includes the obvious smaller aromatic rings (e.g. phenylalanine), indole double rings (e.g. tryptophan), and the less obvious sugars (e.g. galactose), unsaturated lipid/prostaglandins and basic amino acids (lysine and arginine). These are dominant cellular interactions.

The interchangeability of the hydrophobic paddle-binders means that astaxanthene can get its paddles stuck in enzyme or receptor protein active sites that normally bind a wide range of ligands (target small molecules, e.g. enzyme substrates). It is likely, therefore, that astaxanthene has anti-inflammatory activity, because it blocks an inflammatory interaction.

The ubiquity of interactions of terpenoids, based on their general structural properties, also gives these molecules access to cellular cytoplasm. These molecules are too large to diffuse through membranes and if they got half way through, they would be permanently stuck in the membrane. Terpenoids will tend to stick to carrier proteins that have hydrophobic patches or slots. These carriers will transport and internalize terpenoids and other similarly shaped molecules, e.g. steroid hormones.

Metformin, the diabetes drug, is another example of a molecule with a flat, hydrophobic side. It is a stretch to call this an antioxidant, but it is useful for this discussion, since one of my students tested to see it it would stick to a tryptophan in the active site of a classic enzyme, beta-galactosidase. Galactose, in the typical substrate for this enzyme, lactose, will bind to the active site, because of a prominent tryptophan. The shocker is that my student showed that metformin also binds to that same site and competes with lactose. Astaxanthene would also be expected to bind in the same way.

Curcumin is one of the most potent anti-inflammatory compounds and the main ingredient in turmuric, binds to proteins that inhibit the inflammatory transcription factor, NFkB. I would expect astaxanthene to also inhibit NFkB.

Capsaicin is a related molecule that binds to the heat/pain sensor in skin and blocks pain sensation. That is how capsaicin is used as a topical analgesic. Castor oil, ricinoleate, binds to the same sensor and competes with capsaicin and also is an effective pain reliever. Note that ricinoleate is a modified fatty acid that could curl up on the same hydrophobic paddle surface as capsaicin.

The bottom line of this discussion is that if someone tries to convince you that resveratrol, the anti-aging ingredient in wine, is an anti-oxidant, be skeptical. Expect that resveratrol will have numerous interactions with proteins and many of those will not be known.

Synuclein and Amyloid Diseases

NSAIDs, such as ibuprofen and aspirin are possible treatments to inhibit the aggregation of proteins (synuclein, beta amyloid) on charged polymers in amyloid diseases, such as Parkinson’s disease, Alzheimer’s disease, etc. Contradictory studies show that intracellular aggregate formation may be protective, since dimers are more toxic than aggregates.

The list of amyloid diseases is long and there are few effective treatments. In each case a protein starts to accumulate in fibers that form amyloid plaques inside or outside the cells. The large aggregates outside are toxic. Inside it appears that the large aggregates are not as toxic as small clumps, oligomers, of the protein.

The amyloid proteins are stacked up in the fibers in a very organized way, so that the same portions of the protein are lined up on each side of the fibers. Outside the cell, the regions with basic amino acids interact with heparin, and in Alzheimer’s disease, for example, the beta amyloid plaque is half heparin. In test tube experiments, fiber formation from protein solutions is accelerated by adding heparin.

Amyloid fibers also form inside cells in the case of the tau fibers of Alzheimer’s disease or the synuclein aggregates in Parkinson’s disease. In theses cases, there should not be any intracellular heparin, and it is not known what polyanion (RNA?) serves to accelerate fiber formation in these cases.

Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and aspirin, reduce the incidence of Parkinson’s and Alzheimer’s diseases. It has recently been shown that in test tube experiments, NSAIDs also decrease the formation of amyloid fibers from synuclein.

Amyloid fibers can be stained by Congo Red and thioflavin. Curcumin is the active component of tumeric and it has a structure related to Congo Red. Curcumin has been shown in recent studies to block synuclein amyloid formation.

In addition, the heparin in the fiber complexes can be stained with berberine. Berberine is a traditional herbal treatment for arthritis. It would not be surprising if it was also effective against Alzheimer’s amyloid plaque.

The large extracellular plaque aggregates appear to be toxic, but the small, oligomeric aggregate of protein appear to be the toxic form in cells. Recent experiments show that facilitating the formation of large intracellular aggregates minimizes the toxicity in animal models of Huntington’s and Parkinson’s diseases. It appears that the large visible aggregates are not the form that kills the cell.

For the time being, the only safe treatments that focus on amyloid fiber formation are the NSAIDs, curcumin and perhaps berberine.

references:
Hirohata M, Ono K, Morinaga A, Yamada M. 2008. Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. Neuropharmacology 54(3):620-7.

Pandey N, Strider J, Nolan WC, Yan SX, Galvin JE. 2008. Curcumin inhibits aggregation of alpha-synuclein. Acta Neuropathol. 115(4):479-89.

Bodner RA, Outeiro TF, Altmann S, Maxwell MM, Cho SH, Hyman BT, McLean PJ, Young AB, Housman DE, Kazantsev AG. 2006. Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington's and Parkinson's diseases. Proc Natl Acad Sci U S A. 103(11):4246-51.

Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT, Kazantsev AG. 2007. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease. Science. 317(5837):516-9.