X-Message-Number: 31899
Date: Sun, 23 Aug 2009 10:22:36 -0700 (PDT)
From:
Subject: Common Food Dye May Hold Promise In Treating Spinal Cord Inju...
[Here's something to dye for. 8)
Since BBG crosses the blood brain barrier, a strong argument could be
made for including BBG in both wash-out and vitrification solutions.]
ScienceDaily (July 29, 2009) aC” A common food additive that gives M&Ms and
Gatorade their blue tint may offer promise for preventing the additional aC" and
serious aC" secondary damage that immediately follows a traumatic injury to the
spinal cord.
In an article published online in the Proceedings of the National Academy of
Sciences, researchers report that the compound Brilliant Blue G (BBG) stops the
cascade of molecular events that cause secondary damage to the spinal cord in
the hours following a spinal cord injury, an injury known to expand the injured
area in the spinal cord and permanently worsen the paralysis for patients.
This research builds on landmark laboratory findings first reported five years
ago by researchers at the University of Rochester Medical Center. In the August
2004 cover story of Nature Medicine, scientists detailed how ATP, the vital
energy source that keeps our body's cells alive, quickly pours into the area
surrounding a spinal cord injury shortly after it occurs, and paradoxically
kills off what are otherwise healthy and uninjured cells.
This surprising discovery marked a milestone in establishing how secondary
injury occurs in spinal cord patients. It also laid out a potential way to stop
secondary spinal injury, by using oxidized ATP, a compound known to block ATP's
effects. Rats with damaged spinal cords who received an injection of oxidized
ATP were shown to recover much of their limb function, to the point of being
able to walk again, ambulating effectively if not gracefully.
Now, scientists detail the clearing of yet another hurdle in moving this
research closer from bench to bedside by successfully identifying a compound
that could be administered systemically to achieve the same benefit. Previously,
the team needed to inject a compound directly into the injured spinal cord area
to achieve its results.
"While we achieved great results when oxidized ATP was injected directly into
the spinal cord, this method would not be practical for use with spinal
cord-injured patients," said lead researcher Maiken Nedergaard, M.D., D.M.Sc.,
professor of Neurosurgery and director of the Center for Translational
Neuromedicine at the University of Rochester Medical Center. "First, no one
wants to put a needle into a spinal cord that has just been severely injured, so
we knew we needed to find another way to quickly deliver an agent that would
stop ATP from killing healthy motor neurons. Second, the compound we initially
used, oxidized ATP, cannot be injected into the bloodstream because of its
dangerous side effects."
Nedergaard cautions that while this body of work offers a promising new way of
treating spinal cord injury, it is still years away from possible application in
patients. In addition, any potential treatments would only be helpful to people
who have just suffered a spinal cord injury, not for patients whose injury is
more than a day old. Just as clot-busting agents can help patients who have had
a stroke or heart attack who get to an emergency room within a few hours, so a
compound that could stem the damage from ATP might help patients who have had a
spinal cord injury and are treated immediately.
Too Much of a Good Thing
While ATP is usually considered to be helpful to our bodies aC" after all, it's
the main source of energy for all of our body's cells aC" Nedergaard was the
first to uncover its darker side in the spinal cord. Immediately after a spinal
cord injury occurs, ATP surges to the damaged area, at levels hundreds of times
higher than normal. It is this glut of ATP that over-stimulates neurons and
causes them to die from metabolic stress.
Neurons in the spinal cord are so susceptible to ATP because of a molecule known
as "the death receptor." Scientists know that the receptor aC" called P2X7 aC"
plays a role in regulating the deaths of immune cells such as macrophages, but
in 2004, Nedergaard's team discovered that P2X7 also is carried in abundance by
neurons in the spinal cord. P2X7 allows ATP to latch onto motor neurons and send
them the flood of signals that cause their deaths, worsening the spinal cord
injury and resulting paralysis.
So the team set its sights on finding a compound that not only would prevent ATP
from attaching to P2X7, but could be delivered intravenously. In a fluke,
Nedergaard discovered that BBG, a known P2X7R antagonist, is both structurally
and functionally equivalent to the commonly used FD&C blue dye No. 1. Approved
by the Food and Drug Administration as a food additive in 1982, more than 1
million pounds of this dye are consumed yearly in the U.S.; each day, the
average American ingests 16 mgs. of FD&C blue dye No. 1.
"Because BBG is so similar to this commonly used blue food dye, we felt that if
it had the same potency in stopping the secondary injury as oxidized ATP, but
with none of its side effects, then it might be great potential treatment for
cord injury," Nedergaard said.
The team was not disappointed. An intravenous injection of BBG proved to
significantly reduce secondary injury in spinal cord-injured rats, who improved
to the point of being able to walk, though with a limp. Rats that had not
received the BBG solution never regained the ability to walk. There was one side
effect: Rats who were injected with BBG temporarily had a blue tinge to their
skin.
Nedergaard's long-time collaborator on this and other projects, chair of the
University of Rochester Department of Neurology Steven Goldman, M.D., Ph.D.,
adds, "We have no effective treatment now for patients who have an acute spinal
cord injury. Our hope is that this work will lead to a practical, safe agent
that can be given to patients shortly after injury, for the purpose of
decreasing the secondary damage that we have to otherwise expect."
Nedergaard and Goldman believe that further laboratory testing will be needed to
test the safety of BBG and related agents before human clinical trials could
begin. Nonetheless, the investigators are optimistic that with sufficient study,
strategies like this could yield new treatments for acute spinal cord injuries
within the next several years.
Other authors from the University of Rochester Medical Center include Weiguo
Peng, Maria L. Cotrina, Xiaoning Han, Hongmei Yu, Lane Bekar, Livnat Blum,
Takahiro Takano, and Guo-Feng Tia.
The research was supported by the New York State Spinal Cord Injury program, the
Miriam and Sheldon Adelson Medical Research Foundation, and grants from the
National Institutes of Health.
____________________________________________________
Systemic administration of an antagonist of the ATP-sensitive receptor P2X7
improves recovery after spinal cord injury
Weiguo Penga,1, Maria L. Cotrinaa,1, Xiaoning Hana, Hongmei Yua, Lane Bekara,
Livnat Bluma, Takahiro Takanoa, Guo-Feng Tiana, Steven A. Goldmanb,2 and Maiken
Nedergaarda,3
+Author Affiliations
Departments of aNeurosurgery and
bNeurology, Division of Glial Disease and Therapeutics, Center for Translational
Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642
Edited by Pasko Rakic, Yale University School of Medicine, New Haven, CT, and
approved June 11, 2009
a u1W.P. and M.L.C. contributed equally to this work. (received for review March
6, 2009)
Abstract
Traumatic spinal cord injury is characterized by an immediate, irreversible loss
of tissue at the lesion site, as well as a secondary expansion of tissue damage
over time. Although secondary injury should, in principle, be preventable, no
effective treatment options currently exist for patients with acute spinal cord
injury (SCI). Excessive release of ATP by the traumatized tissue, followed by
activation of high-affinity P2X7 receptors, has previously been implicated in
secondary injury, but no clinically relevant strategy by which to antagonize
P2X7 receptors has yet, to the best of our knowledge, been reported. Here we
have tested the neuroprotective effects of a systemically administered P2X7R
antagonist, Brilliant blue G (BBG), in a weight-drop model of thoracic SCI in
rats. Administration of BBG 15 min after injury reduced spinal cord anatomic
damage and improved motor recovery without evident toxicity. Moreover, BBG
treatment directly reduced local activation of astrocytes and microglia, as well
as neutrophil infiltration. These observations suggest that BBG not only
protected spinal cord neurons from purinergic excitotoxicity, but also reduced
local inflammatory responses. Importantly, BBG is a derivative of a commonly
used blue food color (FD&C blue No. 1), which crosses the bloodaC"brain barrier.
Systemic administration of BBG may thus comprise a readily feasible approach by
which to treat traumatic SCI in humans.
FASEB J. 2009 Jun;23(6):1893-906. Epub 2009 Jan 26.
Altered P2X7-receptor level and function in mouse models of Huntington's disease
and therapeutic efficacy of antagonist administration.
DA az-HernA!ndez M, DA ez-Zaera M, SA!nchez-Nogueiro J, GA mez-Villafuertes
R, Canals JM, Alberch J, Miras-Portugal MT, Lucas JJ. Centro de BiologA a
Molecular Severo Ochoa, CSIC/UAM, Campus UAM de Cantoblanco, 28049 Madrid,
Spain.
The precise mechanism by which mutant huntingtin elicits its toxicity
remains unknown. However, synaptic alterations and increased susceptibility
to neuronal death are known contributors to Huntington's disease (HD)
symptomatology. While decreased metabolism has long been associated with HD,
recent findings have surprisingly demonstrated reduced neuronal apoptosis
in Caenorhabditis elegans and Drosophila models of HD by drugs that diminish
ATP production. Interestingly, extracellular ATP has been recently reported
to elicit neuronal death through stimulation of P2X7 receptors. These are
ATP-gated cation channels known to modulate neurotransmitter release from
neuronal presynaptic terminals and to regulate cytokine production and
release from microglia. We hypothesized that alteration in P2X7-mediated
calcium permeability may contribute to HD synaptic dysfunction and increased
neuronal apoptosis. Using mouse and cellular models of HD, we demonstrate
increased P2X7-receptor level and altered P2X7-mediated calcium permeability
in somata and terminals of HD neurons. Furthermore, cultured neurons
expressing mutant huntingtin showed increased susceptibility to apoptosis
triggered by P2X7-receptor stimulation. Finally, in vivo administration of
the P2X7-antagonist Brilliant Blue-G (BBG) to HD mice prevented neuronal
apoptosis and attenuated body weight loss and motor-coordination deficits.
These in vivo data strongly suggest that altered P2X7-receptor level and
function contribute to HD pathogenesis and highlight the therapeutic
potential of P2X7 receptor antagonists.
PMID: 19171786
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