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-- J.R.R. Tolkien The Children of Hurin
- Tau Busters -
General Information:
Names:
Wikipedia entry:
Dr. Ray Shahelien entry:
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Observations:
See also Cinnamon
Methylene Blue
Niacinamide
Grape seed extract
Davunitide
Nypta
Valproic Acid
Tau
Metformin
Epothilone D
Discovery
Of
Molecular Cause Of Alzheimer's Disease Could Bring Early
Diagnosis, Treatment Closer
25 May 2009
... The crucial protein,
called a tau protein, is a normal part of the brain and central
nervous system. But in Alzheimer's patients, tau proteins go out
of control and form tangles that, along with senile plaques, are
the primary cause of the degenerative disease.
Several years ago, it was
discovered that tau proteins in normal brains contain only three
to four attached phosphates, while abnormal tau in Alzheimer's
patients have anywhere from 21 to 25 additional phosphates...
http://www.medicalnewstoday.com/articles/151234.php
The wording describing the action of the first six of these is
almost identical: "capable of inhibiting tau peptide
aggregations, as well as dissociating preformed tau peptide
aggregates".
GSK-3 inhibitor drugs lithium and "NP-12" (Noscira, Spain), may
also prevent tau protein corruption. Lithium has side
effects that make it difficult to use. Clinical trials of
NP-12 are ongoing (as of 3/6/2010). In the clinical
trials, the drug is referred to as "NP031112" NP-12 is the
commonly used name for NP031112. The drug is also known as
Nypta®. The active ingredient is
4-benzyl-2-naphtalen-1-yl-1,2,4-thiadiazolidine-3,5-dione.
Phenothiazine-mediated rescue of cognition in tau transgenic
mice requires neuroprotection and reduced soluble tau burden
It has traditionally been thought that the pathological
accumulation of tau in Alzheimer's disease and other tauopathies
facilitates neurodegeneration, which in turn leads to cognitive
impairment. However, recent evidence suggests that tau tangles
are not the entity responsible for memory loss, rather it is an
intermediate tau species that disrupts neuronal function.
Thus, efforts to discover therapeutics for tauopathies emphasize
soluble tau reductions as well as neuroprotection.
Results: Here, we found that neuroprotection alone caused by
methylene blue (MB), the parent compound of the anti-tau
phenothiaziazine drug, RemberTM, was insufficient to rescue
cognition in a mouse model of the human tauopathy, progressive
supranuclear palsy (PSP) and fronto-temporal dementia with
parkinsonism linked to chromosome 17 (FTDP17): Only when levels
of soluble tau protein were concomitantly reduced by a very high
concentration of MB, was cognitive improvement observed. Thus,
neurodegeneration can be decoupled from tau accumulation, but
phenotypic improvement is only possible when soluble tau levels
are also reduced.
Conclusions: Neuroprotection alone is not sufficient to rescue
tau-induced memory loss in a transgenic mouse model.
Development of neuroprotective agents is an area of intense
investigation in the tauopathy drug discovery field. This may
ultimately be an unsuccessful approach if soluble toxic tau
intermediates are not also reduced.
Thus, MB and related compounds, despite their pleiotropic
nature, may be the proverbial "magic bullet"because they not
only are neuroprotective, but are also able to facilitate
soluble tau clearance. Moreover, this shows that neuroprotection
is possible without reducing tau levels.
This indicates that there is a definitive molecular link between
tau and cell death cascades that can be disrupted.
On page 11 of the article, it says "A treatment of 650mg/day in
a 70kg (154lb) human equates to 9.3mg/kg/day." So, 650mg spread
through the day. However, on Page 2 it says that FDA guidelines
are 10mg/kg (of body mass) for a mouse is equivalent to ~1mg/kg
for a human. This seems to be a contradiction. I'm not sure
where they got that 650mg number from. In the article it
mentions that they were using 5 times the recommended dose. I
don't know where they got the "recommended dose" from. It might
be that they are using this 10:1 mouse to man ratio. It probably
should have been 65mg/day dose for a 70kg human is about 1mg/kg.
Then multiply by 10. The equivalent for a mouse would be about
10mg/day for a mouse. But a short cut to get that number would
be to multiply the human dose by 10 and then divide by the
weight of 70kg. If this is so, 65mg isn't so bad. If I remember
correctly, the clinical trials of Rember (a variation on the
methylene blue theme) used something like 60mg 3 times per day.
There is a post about it on the group's Yahoo web site about 2
years ago.
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Known sources:
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Natural sources:
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References:
Phenothiazine-mediated rescue of
cognition in tau transgenic mice requires neuroprotection and
reduced soluble tau burden.
O'Leary
JC 3rd, Li Q, Marinec P, Blair LJ, Congdon EE, Johnson AG,
Jinwal UK, Koren J 3rd, Jones JR, Kraft C, Peters M, Abisambra
JF, Duff KE, Weeber EJ, Gestwicki JE, Dickey CA.
Mol
Neurodegener. 2010 Nov 1;5:45.Source
Department
of Molecular Medicine, Byrd Alzheimer's Research Institute,
University of South Florida, Tampa, FL 33613, USA.
cdickey@health.usf.edu.
Abstract
BACKGROUND:
It has
traditionally been thought that the pathological accumulation of
tau in Alzheimer's disease and other tauopathies facilitates
neurodegeneration, which in turn leads to cognitive impairment.
However, recent evidence suggests that tau tangles are not the
entity responsible for memory loss, rather it is an intermediate
tau species that disrupts neuronal function. Thus, efforts to
discover therapeutics for tauopathies emphasize soluble tau
reductions as well as neuroprotection.
RESULTS:
Here, we
found that neuroprotection alone caused by methylene blue (MB),
the parent compound of the anti-tau phenothiaziazine drug,
Rember™, was insufficient to rescue cognition in a mouse model
of the human tauopathy, progressive supranuclear palsy (PSP) and
fronto-temporal dementia with parkinsonism linked to chromosome
17 (FTDP17): Only when levels of soluble tau protein were
concomitantly reduced by a very high concentration of MB, was
cognitive improvement observed. Thus, neurodegeneration can be
decoupled from tau accumulation, but phenotypic improvement is
only possible when soluble tau levels are also reduced.
CONCLUSIONS:
Neuroprotection
alone is not sufficient to rescue tau-induced memory loss in a
transgenic mouse model. Development of neuroprotective agents is
an area of intense investigation in the tauopathy drug discovery
field. This may ultimately be an unsuccessful approach if
soluble toxic tau intermediates are not also reduced. Thus, MB
and related compounds, despite their pleiotropic nature, may be
the proverbial "magic bullet" because they not only are
neuroprotective, but are also able to facilitate soluble tau
clearance. Moreover, this shows that neuroprotection is possible
without reducing tau levels. This indicates that there is a
definitive molecular link between tau and cell death cascades
that can be disrupted.
PMID:
21040568 [PubMed] PMCID: PMC2989315
http://www.ncbi.nlm.nih.gov/pubmed/21040568
Full
Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989315/?tool=pubmed
The
characterization of microtubule-stabilizing drugs as possible
therapeutic agents for Alzheimer's disease and related
tauopathies.
Brunden KR, Yao Y, Potuzak
JS, Ferrer NI, Ballatore C, James MJ, Hogan AM, Trojanowski JQ,
Smith AB 3rd, Lee VM.
Pharmacol Res. 2011
Apr;63(4):341-51. Epub 2010 Dec 14.
Source: Center for
Neurodegenerative Disease Research and Institute on Aging,
Department of Pathology and Laboratory Medicine, School of
Medicine, University of Pennsylvania, Philadelphia, PA 19104,
United States. kbrunden@upenn.edu
Abstract
Tau, a protein that is
enriched in neurons of the central nervous system (CNS), is
thought to play a critical role in the stabilization of
microtubules (MTs). Several neurodegenerative disorders referred
to as tauopathies, including Alzheimer's disease and certain
types of frontotemporal lobar degeneration, are characterized by
the intracellular accumulation of hyperphosphorylated tau
fibrils. Tau deposition into insoluble aggregates is believed to
result in a loss of tau function that leads to MT
destabilization, and this could cause neurodegeneration as
intact MTs are required for axonal transport and normal neuron
function. This tau loss-of-function hypothesis has been
validated in a tau transgenic mouse model with spinal cord tau
inclusions, where the MT-stabilizing agent, paclitaxel,
increased spinal nerve MT density and improved motor function
after drug absorption at neuromuscular junctions. Unfortunately,
paclitaxel is a P-glycoprotein substrate and has poor
blood-brain barrier permeability, making it unsuitable for the
treatment of human tauopathies. We therefore examined several
MT-stabilizing compounds from the taxane and epothilone natural
product families to assess their membrane permeability and to
determine whether they act as substrates or inhibitors of
P-glycoprotein. Moreover, we compared brain and plasma levels of
the compounds after administration to mice. Finally, we assessed
whether brain-penetrant compounds could stabilize mouse CNS MTs.
We found that several epothilones have significantly greater
brain penetration than the taxanes. Furthermore, certain
epothilones cause an increase in CNS MT stabilization, with
epothilone D demonstrating a favorable pharmacokinetic and
pharmacodynamic profile which suggests this agent merits further
study as a potential tauopathy drug candidate.
PMID: 21163349 [PubMed]
PMCID: PMC3042036
http://www.ncbi.nlm.nih.gov/pubmed/21163349
Full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042036/?tool=pubmed
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Preface Brain Failure Notes References
pg. 1 References pg. 2
Nutritional Alternatives
Patricia's Protocol
Tauopathy
Discussion
Forum
Correspondence Newsletters Poems Memory Enhancement
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Updated: July 2, 2012
Inception: July 2, 2012