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From: NIH news releases and news items [mailto:[log in to unmask]] On
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Sent: September 12, 2011 09:58
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Subject: NIH-FUNDED RESEARCH POINTS TO POTENTIAL THERAPY FOR
TUMOR-ASSOCIATED EPILEPSY

U.S. Department of Health and Human Services 
NATIONAL INSTITUTES OF HEALTH NIH News 
National Institute of Neurological Disorders and Stroke (NINDS)
<http://www.ninds.nih.gov/>
For Immediate Release: Monday, September 12, 2011

CONTACT: Daniel Stimson, NINDS, 301-496-5751,
<e-mail:[log in to unmask]>

NIH-FUNDED RESEARCH POINTS TO POTENTIAL THERAPY FOR TUMOR-ASSOCIATED
EPILEPSY

Glioma, one of the most deadly and common types of brain tumor, is often
associated with seizures, but the origins of these seizures and effective
treatments for them have been elusive.  Now a team funded by the National
Institutes of Health has found that human gliomas implanted in mice release
excess levels of the brain chemical glutamate, overstimulating neurons near
the tumor and triggering seizures.

The researchers also found that sulfasalazine, a drug on the market for
treating certain inflammatory disorders, can reduce seizures in mice with
glioma.

About 80 percent of people with glioma will experience at least one seizure
during their illness, often as the first symptom.  About one-third of
patients will develop recurring seizures, known as tumor-associated
epilepsy.  Sen. Ted Kennedy, D-Mass., whose death was caused by a malignant
glioma in August 2009, was diagnosed after having a seizure 15 months
earlier. 

"Seizures are a frequent symptom of glioma and are often poorly controlled
by epilepsy medications," said Jane Fountain, Ph.D., a program director at
NIH's National Institute of Neurological Disorders and Stroke (NINDS).
"Understanding why the seizures occur and how to counteract them could help
us substantially improve the quality of life for people with glioma."

"People have assumed that tumors cause seizures by irritating the brain, but
that really isn't a scientific explanation.  We have now shown that the
seizures are caused by glutamate release from the tumor," said Harald
Sontheimer, Ph.D., a professor of neurobiology and director of the Center
for Glial Biology in Medicine at the University of Alabama Birmingham (UAB).
Dr. Sontheimer and his team published their results in Nature Medicine.

The research was supported by NINDS, including $934,698 in grants funded
through the American Recovery and Reinvestment Act.

Glutamate serves as a chemical relay within the brain. Its release from one
neuron can stimulate other neurons to fire electrical impulses.  However,
excess glutamate can cause abnormal electrical activity in the brain - which
is the basis for epileptic seizures.  In particular, excess release of
glutamate from non-neuronal cells called glia appears to play a role in some
types of epilepsy.  Because gliomas result from an overgrowth of glia,
researchers had theorized that glutamate produced by the tumors might cause
seizures, but no one had established a causal link.

Dr. Sontheimer's team tested the theory by studying mice whose brains were
seeded with human glioma cells.  They found that about one-third of the
animals with gliomas developed abnormal brain activity and behavioral signs
consistent with seizures.  They also investigated whether or not the tumors
affect brain activity in response to stimulation. When they delivered
electrical pulses near a tumor, they saw a pattern of activity that spread
outward from the tumor and was more prolonged and widespread than the
responses to stimulation seen in normal brain tissue.  Brain tissue
containing the tumors also released higher levels of glutamate compared to
normal brain tissue.

Next, the researchers sought to determine if the drug sulfasalazine could
correct these abnormalities.  Sulfasalazine is an anti-inflammatory
sometimes prescribed for ulcerative colitis and rheumatoid arthritis.  It
also targets a protein complex called the system Xc(-) transporter.  System
Xc(-) acts like a commodities broker within glioma cells, importing the
essential amino acid cystine into the cells in exchange for exporting
glutamate.

Dr. Sontheimer's team found that by inhibiting the system Xc(-) transporter,
sulfasalazine can reduce glutamate release from gliomas.  The drug also
reduced seizure activity in the glioma-bearing mice, cutting the frequency
of epileptic bursts nearly fivefold in the first hour after treatment.
After four hours, the effects of the drug wore off unless it was
re-administered. The likely reason is that most of the drug is broken down
into a form that does not affect system Xc(-), according to Dr. Sontheimer.


A clinical trial is planned at UAB to determine if sulfasalazine can reduce
seizures in people with slow-growing gliomas.  Meanwhile, Dr. Sontheimer's
lab is working with medicinal chemists to develop a form of the drug that is
more stable in the bloodstream and brain, and more active against system
Xc(-).

"There is hope that in addition to reducing seizures, sulfasalazine might
reduce the growth of glioma cells," Dr. Sontheimer said.  The cystine
molecules imported by system Xc(-) are used to manufacture vital proteins
that help tumor cells grow stronger, he explained.  In a 2005 study, he
found that sulfasalazine delays glioma growth in mice.

Whether these promising results with sulfasalazine in animal studies will
translate into improved outcome in patients with brain tumors remains to be
tested.  Indeed, caution was raised by a small trial of 10 patients with
advanced stage gliomas treated with varying doses of sulfasalazine.  No
beneficial effects were established, and safety concerns arose about whether
treatment worsened brain swelling near the tumor.  That trial was terminated
early.  

"It is worth examining whether or not the drug can help patients with newly
diagnosed, slow-growing gliomas as opposed to patients with advanced
disease," Dr. Sontheimer said. 

The lead author of the study, Susan Buckingham, Ph.D., and second author,
Susan Campbell, Ph.D., received support from the NINDS Training Program in
Brain Tumor Biology at UAB.  Vedrana Montana, Ph.D., was hired as a
postdoctoral fellow in the Center for Glial Biology in Medicine through
Recovery Act funds.    The work was also supported by a center core grant
from the NIH Blueprint for Neuroscience Research.

For more information about brain tumors, please visit
<http://www.ninds.nih.gov/disorders/brainandspinaltumors/brainandspinaltumor
s.htm>.

NINDS (www.ninds.nih.gov) is the nation's leading funder of research on the
brain and nervous system.  The NINDS mission is to reduce the burden of
neurological disease - a burden borne by every age group, by every segment
of society, by people all over the world.

The NIH Blueprint for Neuroscience Research
(www.neuroscienceblueprint.nih.gov) is a cooperative effort among the NIH
Office of the Director and the 15 NIH Institutes and Centers that support
research on the nervous system. By pooling resources and expertise, the
Blueprint supports transformative neuroscience research, and the development
of new tools, training opportunities, and other resources to assist
neuroscientists.

About the National Institutes of Health (NIH): NIH, the nation's medical
research agency, includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. NIH is the primary federal
agency conducting and supporting basic, clinical, and translational medical
research, and is investigating the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and its programs,
visit <www.nih.gov>.
----------------------------
REFERENCES:

Buckingham SC et al.  "Glutamate Release by Primary Brain Tumors Induces
Epileptic Activity."  Nature Medicine, published online September 11, 2011.

Robe PA et al.  "Early termination of ISRCTN45828668, a phase 1/2
prospective, randomized study of sulfasalazine for the treatment of
progressing malignant gliomas in adults."  BMC Cancer, October 2009.

---------------------------
This release contains a photo at
<http://www.ninds.nih.gov/img/glioma_glutamate_seizures.jpg>. Caption: After
electrical stimulation, there is a prolonged, broader spread of activity
(yellow and red areas) in mouse brain tissue containing a glioma (left)
compared to normal mouse brain tissue (right). Adjacent frames are 1.8
milliseconds apart.  Courtesy of Dr. Harald Sontheimer, University of
Alabama Birmingham.
----------------------------
The activities described in this release are funded in part through the
American Recovery and Reinvestment Act. More information about NIH's
Recovery Act grant funding opportunities can be found at
<http://grants.nih.gov/recovery/>. To track the progress of HHS activities
funded through the Recovery Act, visit <www.hhs.gov/recovery>. To track all
federal funds provided through the Recovery Act, visit <www.recovery.gov>.

##

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<http://www.nih.gov/news/health/sep2011/ninds-12.htm>.

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