Tau busters

[Swarfmaker]

There are now four substances that might be effective in preventing or
even eliminating tau protein corruption:

Cinnamon proanthocyanidins... from any species of cinnamon
Methylene blue... an old prescription medication
Niacinamide... a variant of Vitamin B3
... and introducing # 4... grape seed extract!

The following messages appeared on the Yahoo "PSPinformatin"
discussion group yesterday:

**********************************************************************
I did a quick search with Google. This is all I came up with, but I
probably missed something:

"Grape Seed Polyphenolic Extract as a Potential Novel Therapeutic
Agent in Tauopathies"
Journal Journal of Alzheimer's Disease
Publisher IOS Press
ISSN 1387-2877 (Print) 1875-8908 (Online)
Issue Volume 16, Number 2 / 2009
Pages 433-439

Abstract: "Abnormal misfoldings of the microtubule-associated protein
tau, leading to the aggregation of tau into paired helical filaments
that are ultimately deposited as neurofibrillary tangles, is a key
neuropathologic feature of a number of neurodegenerative disorders
collectively referred to as tauopathies. We recently observed that a
particular grape seed polyphenolic extract (GSPE), namely, Meganatural-
Az® may attenuate the generation and stability of misfolded proteins.
We hypothesized that Meganatural-Az® GSPE might also attenuate tau
protein misfolding that leads to the generation of tau filamentary
aggregates that are critical for the initiation and progression of
neurodegeneration and/or cognitive dysfunctions in tauopathies. In
this study, we used in vitro aggregations of synthetic Ac-^{306}
VQIVYK^{311} tau peptide as a model system to explore whether
Meganatural-Az® GSPE might modulate aggregations of tau protein. We
demonstrate that this GSPE is capable of inhibiting tau peptide
aggregations, as well as dissociating preformed tau peptide
aggregates. Results from this study suggest that this GSPE might
provide beneficial disease-modifying bioactivities in tau-associated
neurodegenerative disorders by modulating tau-mediated neuropathologic
mechanisms. Our observation, in conjunction with the emonstrated
bioavailability, as well as safety and tolerability, of this GSPE,
supports the development of Meganatural-Az® GSPE for the prevention
and/or treatment of tau-associated neurodegenerative disorders."
http://iospress.metapress.com/content/fq65p9545646548m/

This brings to four the number of substances we have heard about in
just over a year's time that might be tau-busters. The other three are
cinnamon proanthocyanidins, methylene blue, and niacinamide. The
wording describing the action of all four is almost identical:
"capable of inhibiting tau peptide aggregations, as well as
dissociating preformed tau peptide aggregates"

--- In pspinfo...@yahoogroups.com, Connie Arizzo <conniearz@...>
wrote:
>
> Aletta, My nephew, a research doctor attended a seminar about psp. He had heard of the disease, but took more interest in it when my husband was diagnosed with it. He said that grape seed extract given to mice and rats in the laboratory reversed the symtoms in psp. It did not cure it, but the lab animals were able to function again with less help. However, the extract has not been tested in humans. He suggested to me that my husband take six pills a day, 2 each morning, noon and night. He said the pills would not hurt him as they are just grape seed extract, and it would take months to see a difference, if any. Since we are both home bound I put him on the extract so now, its a wait and see situation. The extract can be purchased at Sam's club, costco, bj's etc. very cheaply. Time will tell.
>
>

This article showed up on another message board I frequent. It is a
press release from a company called Allon Therapeutics Inc. about
another potential tau-buster drug by the name of davunetide intranasal
(AL-108). They are conducting a clinical trial for a tauopathy FTD
called PSP (progressive supranuclear palsy).
http://allontherapeutics.com/ir_news_25Jun_2009.html

If the reason that Rember appeared to be effective was because of its
effect on the Helicobacter pylori (and the resulting reduction in
TNF), not on its ability to "prevent tau aggregation and disaggregate
aggregations already formed", then I expect the results of their
clinical trial will be disappointing. However, if it does pan out,
then this will support the rationale for attacking the tau problem.

So, now we have 5 potential tau-busters: cinnamon proanthocyanidins,
methylene blue, niacinamide, grape seed extract, and davunetide.
Anyone who holds the opinion that davunetide has the possibility to be
effective because of its effect on the tau protein problem of
tauopathies should also be encouraged to know that the other potential
tau-busters are MUCH easier to obtain than davunetide.

Apparently, there will be a clinical trial for davunetide. You can get
the details from this web site:


Davunetide (AL-108) in Predicted Tauopathies - Pilot Study
This study is currently recruiting participants.
Verified by University of California, San Francisco, January 2010
http://clinicaltrials.gov/ct2/show/NCT01056965

There are so many requirements and exclusion criteria that considering
how rare CBD is, I have to wonder if they will find more than 2 or 3
people for this trial.

It is interesting to note these two "exclusion criteria", #5 & #6:

5.Within 4 weeks of screening or during the course of the study,
concurrent treatment with memantine, acetylcholinesterase inhibitors,
antipsychotic agents or mood stabilizers (valproate, lithium, etc.) or
benzodiazepines (other than temazepam or zolpidem).

6.Treatment with lithium, methylene blue, tramiprosate, ketone bodies,
Dimebon or any putative disease-modifying agent directed at tau within
90 days of screening.

I know about lithium and methylene blue. "Ketone bodies" is a way to
describe the use of medium chain triglycerides (MCTs) such ax caprylic
(fatty) acid, coconut oil, MCT oils, and Axona. I didn't know that
"ketone bodies" therapy would would affect the corrupted tau problem,
but then I guess it makes sense that it could.

"Tramiprosate" is new to me.

According to Wikipedia:

Homotaurine (also spelled homotaurin, aka Tramiprosate) is a synthetic
organic compound. It is analogous to taurine, but with an extra carbon
in its chain. Because of its similarity in structure to the
neurotransmitter gamma-aminobutyric acid (GABA), it has GABAergic
effects and may be useful as an anticonvulsant.

Homotaurine is also being investigated as a potential treatment for
Alzheimer's disease. It binds to soluble amyloid beta and inhibits the
formation of neurotoxic aggregates that lead to amyloid plaque
deposition in the brain.

Homotaurine is a zwitterion at neutral pH.
http://en.wikipedia.org/wiki/Homotaurine

I'm going to have to look into this one some more.

This article deals more with amyloid beta, but it mentions that levels
of the chemical in grape seed extract in the brain rise with "chronic
consumption"...

How To Boost Value Of Alzheimer's-fighting Compounds
ScienceDaily (Aug. 17, 2009) — The polyphenols found in red wine are
thought to help prevent Alzheimer's disease, and new research from
Purdue University and Mount Sinai School of Medicine has shown that
some of those compounds in fact reach the brain.

Mario Ferruzzi, a Purdue associate professor of food science; Connie
Weaver, Purdue's head of foods and nutrition; and Elsa Janle, a Purdue
associate professor of foods and nutrition, found that the amount of
polyphenols from grapeseed extract that can reach a rat's brain is as
much as 200 percent higher on the 10th consecutive day of feeding as
compared to the first. Many previous experiments, in which absorption
was measured after single or sporadic doses, often found very little,
if any, of the bioactive polyphenols reaching brain tissues. However,
more chronic exposure appears to improve absorption...
http://www.sciencedaily.com/releases/2009/08/090817143604.htm

I can not find much information about what this "Meganatural-Az" is,
other than a code name for some component of grape seed extract being
investigated for its potential effect on tau pathology. Normally, I
don't feel there is much benefit delving into something that is not
readily available as a pharmaceutical or a supplement since my
objective is to help someone who is afflicted with a neurodegenerative
disease NOW. My interest in this comes down to the simple question,
could a person get enough of whatever this "Meganatural-Az" is from
the grape seed exctracts already available? What about from red wine
or from grape juice?

I have not been able to obtain the full text of the paper mentioned
below yet.

Some more on grape seed extract....

J Neurochem. 2010 Jun 20. [Epub ahead of print]
Development of a grape seed polyphenolic extract with anti-oligomeric
activity as a novel treatment in progressive supranuclear palsy and
other tauopathies.

Pasinetti GM, Ksiezak-Reding H, Santa-Maria I, Wang J, Ho L.

Center of Excellence for Novel Approaches to Neurodiagnostics and
Neurotherapeutics, Brain Institute, Center of Excellence for Research
in Complementary and Alternative Medicine in Alzheimer's Disease,
Department of Neurology, Mount Sinai School of Medicine, 1 Gustave L.
Levy Place, Box 1137,
New York, NY 10029, USA.
Abstract

A diverse group of neurodegenerative diseases - including progressive
supranuclear palsy (PSP), corticobasal degeneration (CBD) and
Alzheimer's disease (AD) among others, collectively referred to as
tauopathies - are characterized by progressive, age-dependent
intracellular formations of misfolded protein aggregates that play key
roles in the initiation and progression of neuropathogenesis. Recent
studies from our laboratory reveal that grape seed-derived
polyphenolic extracts (GSPE) potently prevent tau fibrillization into
neurotoxic aggregates and therapeutically promote the dissociation of
preformed tau aggregates (Ho et al., 2009). Based on our extensive
bioavailability, bioactivity and functional pre-clinical studies,
combined with the safety of GSPE in laboratory animals and in humans,
we initiated a series of studies exploring the role of GSPE
(Meganatural-Az((R)) GSPE) as a potential novel botanical drug for the
treatment of certain forms of tauopathies including PSP, a
neurodegenerative disorder involving the accumulation and deposition
of misfolded tau proteins in the brain characterized, in part, by
abnormal intracellular tau inclusions in specific anatomical areas
involving astrocytes, oligodendrocytes and neurons (Takahashi et al.,
2002). In this mini-review article, we discuss the biochemical
characterization of GSPE in our laboratory and its potential
preventative and therapeutic role in model systems of abnormal tau
processing pertinent to PSP and related tauopathies.

PMID: 20569300 [PubMed]
http://www.ncbi.nlm.nih.gov/pubmed/20569300

Here is a link to the article about grape seed extract...

"Development of a grape seed polyphenolic extract with anti-oligomeric
activity as a novel treatment in progressive supranuclear palsy and
other tauopathies"

Giulio Maria Pasinetti1,*, Hanna Ksiezak-Reding, Ismael Santa-Maria,
Jun Wang,
Lap Ho

(This is an Accepted Article that has been peer-reviewed and approved
for publication in the Journal of Neurochemistry, but has yet to
undergo copy-editing and proof correction. Please cite this article as
an "Accepted Article"; doi: 10.1111/j.1471-4159.2010.06875.)

http://www3.interscience.wiley.com/cgi-bin/fulltext/123546662/PDFSTART