Methylene Blue

www.perpetualcommotion.com
"Give with a free hand, but give only your own."
-- J.R.R. Tolkien The Children of Hurin
- Methylene Blue -

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Observations:

"In the trial reported here, 321 patients were randomized to 30 mg, 50 mg, 100 mg or placebo. The drug, Dr. Wischik said, was effective when it dissolved in the stomach, but was not effective when the drug was absorbed through the intestines. This was an issue for the 100-mg dose, which had 'absolutely no activity because it didn't dissolve in the stomach.'"
http://www.medpagetoday.com/MeetingCoverage/ICAD/10320

As I wrote elsewhere, the Helicobacter pylori bacteria finds methylene blue to be rather toxic. This tends to support the idea that the dominant effect may not have been as a "Tau aggregation inhibitor (TAI)", but rather as an antibiotic. This would explain why the 100mg dose was not effective when it dissolved in the intestines, whereas the 30 and 60mg doses, which disolved in the stomach, were effective. The antibiotic effect of the rember (which is basically methylene blue) reduced the H.pylori infection, thereby reducing the TNF levels. It seems to me that anyone getting Enbrel injections to reduce TNF levels should take a hard look at this.

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Methylene Blue

See also Rember
       Helicobacter pylori
       Hsp70
         Tau Busters
         Mitochondrial Dysfunction

Potential Alzheimer's, Parkinson's Cure Found In Century-old Drug
ScienceDaily (Aug. 18, 2008)
"A new study conducted by researchers at Children's Hospital & Research Center Oakland shows that a century-old drug, methylene blue, may be able to slow or even cure Alzheimer's and Parkinson's disease. Used at a very low concentration – about the equivalent of a few raindrops in four Olympic-sized swimming pools of water – the drug slows cellular aging and enhances mitochondrial function, potentially allowing those with the diseases to live longer, healthier lives."

"Methylene blue, first discovered in 1891, is now used to treat methemoglobinemia, a blood disorder. But because high concentrations of methylene blue were known to damage the brain, no one thought to experiment with low concentrations. Also, drugs such as methylene blue do not easily reach the brain."
http://www.sciencedaily.com/releases/2008/08/080818101335.htm

No mention in the full article of its possible effect on tau, which, given the close connection between Rember and methylene blue, is interesting.

Given this new piece of information, and the other article about Rember, I checked into the availability of methylene blue.

"Methylene blue has been around forever, used for urinary tract infections, malaria, and all sorts of things, up to treating protozoal infections in fish tanks. (For that matter, it's turned up over the years as a surreptitious additive to blueberry pies and the like, turning the unsuspecting consumer's urine greenish/blue, generally to their great alarm: a storied med school prank from the old days)."
http://pipeline.corante.com/archives/2008/07/31/rember_for_alzheimers_methylene_blues_comeback.php

Sure enough, methylene blue is available from pet supply stores. Here is an example:
http://www.petsolutions.com/default.aspx?ItemId=64000052&EID=SZ64000052&SID=SHZIL

I don't know if I would try this pet store MB or not. I offer it only for your information. It doesn't seem to hurt fish. But according to that other article from Science Daily on August 18, it is "used at a very low concentration – about the equivalent of a few raindrops in four Olympic-sized swimming pools of water". Seems kind of dilute to me.

PMID: 17721552 IC50 for MAO A inhibition is 164 nM: an order of magnitude lower than that needed to prevent tau filament formation.

Patent 7,335,505 Reduced methylene blue (leucomethylene blue) is more effective and crosses the blood brain barrier better. One recipe for reduction is 2 - 2.5 mg vitamin C per mg MB for three hours. IC50 for inhibiting tau filament formation is 4 microM.

PMID: 15611092 Myricetin is actually better than MB for inhibiting tau filament formation (IC50s of 1.2 and 1.9 microM).

PMID: 14666245 Myricetin probably needs something like a lecithin liposome to cross the blood brain barrier. (Quercetin does.) Let's badger Source Naturals into providing this formulation, since their myricetin product is a tablet. (With a very nice banana smell.)

TauRx's second generation drug is called LMT-X. My guess from the name is that it's a shelf-stable leucomethylene blue formulation.
http://www.longecity.org/forum/topic/23947-methylene-blue-research/

Here is a message Sharon Comden posted to the Yahoo Tauopathies group on Aug 7, 2013:

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Known sources:

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Natural sources:

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References:

Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo.
Erin E Congdon, Jessica W Wu, Natura Myeku, Yvette H Figueroa, Mathieu Herman, Paul S Marinec, Jason E Gestwicki, Chad A Dickey, W Haung Yu, Karen Duff
Autophagy. 2012 Apr 1;8 (4): 22361619
Taub Institute/Department of Pathology; Columbia University and Department of Integrative Neuroscience; New York State Psychiatric Institute; New York, NY USA.

More than 30 neurodegenerative diseases including Alzheimer disease (AD), frontotemporal lobe dementia (FTD), and some forms of Parkinson disease (PD) are characterized by the accumulation of an aggregated form of the microtubule-binding protein tau in neurites and as intracellular lesions called neurofibrillary tangles. Diseases with abnormal tau as part of the pathology are collectively known as the tauopathies. Methylthioninium chloride, also known as methylene blue (MB), has been shown to reduce tau levels in vitro and in vivo and several different mechanisms of action have been proposed. Herein we demonstrate that autophagy is a novel mechanism by which MB can reduce tau levels. Incubation with nanomolar concentrations of MB was sufficient to significantly reduce levels of tau both in organotypic brain slice cultures from a mouse model of FTD, and in cell models. Concomitantly, MB treatment altered the levels of LC3-II, cathepsin D, Beclin 1, and p62 suggesting that it was a potent inducer of autophagy. Further analysis of the signaling pathways induced by MB suggested a mode of action similar to rapamycin. Results were recapitulated in a transgenic mouse model of tauopathy administered MB orally at three different doses for two weeks. These data support the use of this drug as a therapeutic agent in neurodegenerative diseases.

Keywords: autophagy; tau; tauopathy; ftd; methylene blue; methylene; induce autophagy; tau level; blue; chloride; beclin; cathepsin; disease; vivo; attenuate;
http://lib.bioinfo.pl/paper:22361619
[See also the “Latest similar papers:” and “Other papers by authors:” sections of the above web page.]

Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo.
Congdon EE, Wu JW, Myeku N, Figueroa YH, Herman M, Marinec PS, Gestwicki JE, Dickey CA, Yu WH, Duff K.
Autophagy. 2012 Apr 1;8(4). [Epub ahead of print]
Source: Taub Institute/Department of Pathology; Columbia University and Department of Integrative Neuroscience; New York State Psychiatric Institute; New York, NY USA.

Abstract
More than 30 neurodegenerative diseases including Alzheimer disease (AD), frontotemporal lobe dementia (FTD), and some forms of Parkinson disease (PD) are characterized by the accumulation of an aggregated form of the microtubule-binding protein tau in neurites and as intracellular lesions called neurofibrillary tangles. Diseases with abnormal tau as part of the pathology are collectively known as the tauopathies. Methylthioninium chloride, also known as methylene blue (MB), has been shown to reduce tau levels in vitro and in vivo and several different mechanisms of action have been proposed. Herein we demonstrate that autophagy is a novel mechanism by which MB can reduce tau levels. Incubation with nanomolar concentrations of MB was sufficient to significantly reduce levels of tau both in organotypic brain slice cultures from a mouse model of FTD, and in cell models. Concomitantly, MB treatment altered the levels of LC3-II, cathepsin D, Beclin 1, and p62 suggesting that it was a potent inducer of autophagy. Further analysis of the signaling pathways induced by MB suggested a mode of action similar to rapamycin. Results were recapitulated in a transgenic mouse model of tauopathy administered MB orally at three different doses for two weeks. These data support the use of this drug as a therapeutic agent in neurodegenerative diseases.
PMID: 22361619 [PubMed]
http://www.ncbi.nlm.nih.gov/pubmed/22361619

Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins.
Taniguchi S, Suzuki N, Masuda M, Hisanaga S, Iwatsubo T, Goedert M, Hasegawa M.

J Biol Chem. 2005 Mar 4;280(9):7614-23. Epub 2004 Dec 17.
Source: Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan.
Abstract
Tau protein is the major component of the intraneuronal filamentous inclusions that constitute defining neuropathological characteristics of Alzheimer's disease and other tauopathies. The discovery of tau gene mutations in familial forms of frontotemporal dementia has established that dysfunction of the tau protein is sufficient to cause neurodegeneration and dementia. Here we have tested 42 compounds belonging to nine different chemical classes for their ability to inhibit heparin-induced assembly of tau into filaments in vitro. Several phenothiazines (methylene blue, azure A, azure B, and quinacrine mustard), polyphenols (myricetin, epicatechin 5-gallate, gossypetin, and 2,3,4,2',4'-pentahydroxybenzophenone), and the porphyrin ferric dehydroporphyrin IX inhibited tau filament formation with IC(50) values in the low micromolar range as assessed by thioflavin S fluorescence, electron microscopy, and Sarkosyl insolubility. Disassembly of tau filaments was observed in the presence of the porphyrin phthalocyanine. Compounds that inhibited tau filament assembly were also found to inhibit the formation of Abeta fibrils. Biochemical analysis revealed the formation of soluble oligomeric tau in the presence of the inhibitory compounds, suggesting that this may be the mechanism by which tau filament formation is inhibited. The compounds investigated did not affect the ability of tau to interact with microtubules. Identification of small molecule inhibitors of heparin-induced assembly of tau will form a starting point for the development of mechanism-based therapies for the tauopathies.
PMID: 15611092 [PubMed]
http://www.ncbi.nlm.nih.gov/pubmed/15611092
Full text: http://www.jbc.org/content/280/9/7614.long

Methylene Blue:
Potential Alzheimer's, Parkinson's Cure Found In Century-old Drug
ScienceDaily (Aug. 18, 2008)
"A new study conducted by researchers at Children's Hospital & Research Center Oakland shows that a century-old drug, methylene blue, may be able to slow or even cure Alzheimer's and Parkinson's disease. Used at a very low concentration – about the equivalent of a few raindrops in four Olympic-sized swimming pools of water – the drug slows cellular aging and enhances mitochondrial function, potentially allowing those with the diseases to live longer, healthier lives."

"Methylene blue, first discovered in 1891, is now used to treat methemoglobinemia, a blood disorder. But because high concentrations of methylene blue were known to damage the brain, no one thought to experiment with low concentrations. Also, drugs such as methylene blue do not easily reach the brain."
http://www.sciencedaily.com/releases/2008/08/080818101335.htm

No mention in the full article of its possible effect on tau, which, given the close connection between Rember and methylene blue, is interesting.

Rember:

Daily pill that halts Alzheimer's is hailed as 'biggest breakthrough against disease for 100 years'
Daily Mail (UK)
By Jenny Hope
Last updated at 11:57 PM on 29th July 2008
(excerpts:)
"A new drug halts the devastating progress of Alzheimer's disease, say British scientists.

"It is said to be more than twice as effective as current treatments.

"A daily capsule of rember [sic], as the drug is known, stops Alzheimer's disease progressing by as much as 81 per cent, according to trial results.

"Patients with the brain disorder had no significant decline in their mental function over a 19-month period.

"It is the first time medication has been developed to target the `tangles' in the brain that destroy nerve cells, leading to deteriorating memory.

"The drug helps to disrupt this process, preventing the formation of new tangles and loosening those already created."
http://www.dailymail.co.uk/health/article-1039677/Daily-pill-halts-Alzheimers-hailed-biggest-breakthrough-disease-100-years.html

errrr... no it isn't the "first time". The "water soluble component of common cinnamon" identified by Prof. Graves at the University of California in Santa Barbara also "inhibits the aggregation of tau and disassembles fibers that have already formed".

If this drug from the UK works, and I certainly hope that it does, then the water-soluble cinnamon extract should too. And we have anecdotal evidence that it does.

What this means is, don't despair that you can't get this new wonder drug. You have alternatives! Check out cinnamon proanthocyanidins and niacinamide.

Rember for Alzheimer's: Methylene Blue's Comeback
corante.com July 31, 2008
"Methylene blue has been around forever, used for urinary tract infections, malaria, and all sorts of things, up to treating protozoal infections in fish tanks. (For that matter, it's turned up over the years as a surreptitious additive to blueberry pies and the like, turning the unsuspecting consumer's urine greenish/blue, generally to their great alarm: a storied med school prank from the old days)."
http://pipeline.corante.com/archives/2008/07/31/rember_for_alzheimers_methylene_blues_comeback.php

Vienna (and Burkina Faso): What's New With Methylene Blue?
Alzheimer Research Forum
30 July 2009
At ICAD in Vienna, Wischik discussed further analysis of the same Phase 2 trial of RemberTM, his biotech company's patented formulation of methylene blue. Wischik noted in his talk that the company had patented a new form called leuco-methylthioninium or LMT, which is no longer blue and renders the drug more bioavailable and less toxic at higher doses. For their part, Schirmer's group had characterized a reduced white version of methylene blue (called leucoMB or methylene white) as a possibly superior form of this drug for use in a colorless drug syrup to treat malaria (see Buchholz et al., 2008 and Schirmer essay). TauRx's new formulation is presently undergoing preclinical studies. For a detailed first-person account of what happened with the high dose of RemberTM in the Phase 2 trial and related topics...
http://www.alzforum.org/new/detail.asp?id=2203

"The WSJ article was a bit misleading because many respected researchers accept that tau is a major player in disability from Alzheimer's. Several reports that I've seen implicate soluble tau as the culprit in functional impacts. The group at the University of Pennsylvania working on Epothilone D and other respected labs are following that hypothesis. Curcumin and methylene blue both decrease soluble tau and improve function in several animal model studies."

"Work is being done in multiple labs on methylene blue. While the rember trial yielded some encouraging results, Dr. Wischik's claim to actually dissolving tau tangles or NFTs has not been replicated in studies that I have reviewed(O'Leary/Chad Dickey, Kumar&Atamna). Until we understand the implications of flooding neurons with soluble tau from "dissolved" NFTs, I would be cautious about that as a therapeutic goal. Reducing soluble tau is within our reach today but more research like Dr. Wischik's is needed to fill in the holes that are mentioned in the WSJ article."

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