Joined: 4/24/2012
Posts: 484
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Two new drugs currently in clinical trials are both using the activation of autophagy in neurons to treat neurodegeneration.Both of these drugs are currently used for cancer treatment, and thus would be available off label.
Will Tau Drug Show Its True Colors in Phase 3 Trials?
"2 October 2012. Remember Rember®—the blue dye that made headlines in
2008 when Phase 2 clinical trial data suggested it slowed decline in
people with Alzheimer’s disease (see ARF related news story)?
A revamped version of this compound, which presumably inhibits tau
aggregation, is now heading toward Phase 3 testing, though in a
different tauopathy. TauRx Therapeutics—a Singapore-based biotech
company with research operations in Scotland—announced last month that
it received U.S. and European regulatory approval to launch a 12-month,
global Phase 3 trial
of its experimental drug in behavioral-variant frontotemporal dementia
(bvFTD). “The FTD field is excited to finally have an agent worthy of a
clinical trial as a potential disease-modifying agent. This is a big
deal,” said Bradley Boeve of Mayo Clinic, Rochester, Minnesota."
http://www.alzforum.org/new/detail.asp?id=3283
The drug is known as methylthioninium chloride, and here is the journal article describing it's possible benefits.
Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo.
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, BECN1, 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."
http://www.ncbi.nlm.nih.gov/pubmed/22361619
The other drug is Nilotinib. Tests are for Parkinson's, but the similarity is that it is removing a mis-folded, toxic protein from the brain through activation of autophagy.
Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson's
disease models
Abstract
"Parkinson's disease is a movement disorder
characterized by death of dopaminergic substantia nigra (SN) neurons
and brain
accumulation of α-synuclein. The tyrosine kinase
Abl is activated in neurodegeneration. Here, we show that lentiviral
expression
of α-synuclein in the mouse SN leads to Abl
activation (phosphorylation) and lentiviral Abl expression increases
α-synuclein
levels, in agreement with Abl activation in PD
brains. Administration of the tyrosine kinase inhibitor nilotinib
decreases
Abl activity and ameliorates autophagic clearance
of α-synuclein in transgenic and lentiviral gene transfer models.
Subcellular
fractionation shows accumulation of α-synuclein and
hyper-phosphorylated Tau (p-Tau) in autophagic vacuoles in α-synuclein
expressing brains, but nilotinib enhances protein
deposition into the lysosomes. Nilotinib is used for adult leukemia
treatment
and it enters the brain within US Food and Drug
Administration approved doses, leading to autophagic degradation of
α-synuclein,
protection of SN neurons and amelioration of motor
performance. These data suggest that nilotinib may be a therapeutic
strategy
to degrade α-synuclein in PD and other
α-synucleinopathies."
http://hmg.oxfordjournals.org/content/early/2013/05/09/hmg.ddt192.abstract
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Joined: 12/12/2011
Posts: 5179
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These drugs may reflect a different side of autophagy--not by increasing the body's immune system (although this cannot be ruled out) to remove amyloid plaques, hyperphosphorylated tau proteins, and aggregated alpha synuclein proteins, but by allowing the body to do the job itself. In all three cases, nitration impedes the clearance or rearrangement of these altered proteins. And methylene blue (Rember) and Nilotinib reduce nitration so that amyloid plaques can potentially be cleared and hyperphosphorylated tau protein and alpha synuclein aggregates can be reconstituted.
Methylene blue inhibits the increase of inducible nitric oxide synthase activity induced by stress and lipopolysaccharide in the medial basal hypothalamus of rats.
http://www.ncbi.nlm.nih.gov/pubmed/11124577
Importantly, nilotinib caused down-regulation of the inflammatory cytokines TNF-α, TGF-β(1) and iNOS levels in the lung.
http://www.ncbi.nlm.nih.gov/pubmed/21473879
Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation.
http://www.ncbi.nlm.nih.gov/pubmed/21903077
Further studies demonstrated that the hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis.
http://www.ncbi.nlm.nih.gov/pubmed/16816118
In fact, nitration of -synuclein tyrosine residues 39, 125, 133 or 136, may be an early event in aggregates,
Lewy bodies, seen in PD. Furthermore, nitrative
stress leads to the induction of -synuclein aggregation at a higher rate than seen in other PD
mutants. This aggregation may result from a
stabilization of pre-assembled -synuclein filaments, which, upon nitration, may withstand
denaturing conditions and enhance formation of
SDS-insoluble, heat-stable high mass aggregates.
http://new.lakeforest.edu/images/userImages/eukaryon/Page_7190/p.%2090-94%20Valtierra%20Review%20PD.pdf
So perhaps if you de-nitrate amyloid plaques, hyperphosphorylated tau proteins, and alpha-synuclein aggregates, the body can clear or reconstitute these proteins. At the very least, the drugs mentioned here would reduce further nitration.
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