Mission: Translational
Brain teaser
How can cancer patients protect their brains from radiation treatment’s
harmful effects? The answer might lie in your medicine cabinet
By Amy Adams
Photograph by Leslie Williamson
SIDEBAR:
Balming out brain disease: more reasons to soothe an inflamed brain
Louis Pasteur once said that chance favors the prepared mind. For graduate
student Michelle Monje, that preparation came from time spent in a neurology
clinic. And what chanced to cross her mind was a new idea about how the
brain heals after an injury.
In 2001 Monje was a medical student doing a rotation in pediatric oncology.
There she met kids going through radiation therapy to treat cancer in
their brain. Although the treatment often cured the cancer, it also left
the children with lifelong learning and memory problems. The fact that
the treatment itself caused enduring harm haunted Monje. “We were
causing permanent brain damage and we didn’t understand the process,” she
says.
Conventional wisdom held that the radiation damaged blood vessels and
injured the cells that surround and insulate neurons, causing the learning
and memory problems. This is where her prepared mind came to bear. Monje
had just completed a rotation in neurology where she learned to identify
brain damage using MRI scans — but she didn’t see any telltale
signs of damaged blood vessels or uninsulated neurons in the children’s
scans.
“Their brains didn’t look that bad, so the explanation didn’t
make any sense,” Monje says.
Her search for a better explanation led Monje to the lab of Theo Palmer,
PhD, assistant professor of neurosurgery, where she is now finishing
the PhD portion of her MD/PhD. Along with colleagues at UC-San Francisco
who were also curious about how radiation damaged the brain, Monje and
Palmer have zeroed in on one phenomenon that seems at fault in preventing
the brain from healing: radiation-induced inflammation. Their work has
since spawned projects investigating the role of inflammation in other
brain disorders and will head back to the clinic this year as part of
a trial in kids receiving radiation treatment for cancer.
Inflaming the brain
When Monje first joined the Palmer lab, she began examining rats whose
brains had received doses of radiation equivalent to those experienced
by children with brain cancer. Along with collaborators at UCSF, Monje
and Palmer studied the brains of these rats, focusing on the hippocampus
because of its crucial role in memory and learning.
There they found problems. The brain’s repair crew of stem cells
started off on the right track by dividing to make more cells, but instead
of maturing into neurons they joined the brain’s support structure
as glial cells. These cells form the brain’s scaffolding but don’t
transmit information.
This failure of stem cells to create new neurons within damaged regions
of the brain could explain why transplanted brain stem cells have failed
to flourish in previous experiments, Monje says. “The stem cells
are still there, but they can’t do their job,” she says. “Something
is wrong in the environment where the stem cells should be making neurons.”
Soon before Monje published these results in 2002, she read a paper
by a group at the Salk Institute in San Diego reporting that a molecule
produced by immune cells called interleukin-6, or IL-6, prevents neural
stem cells from turning into neurons in mice. That same week, Monje had
noticed immune cells in the brains of her irradiated rats. “A lot
of things started happening at once,” Monje says.
With the tip-off that immune cells might be involved, everything fell
into place. Monje remembered that people with Alzheimer’s disease
often fare better when they receive an immune cell-fighting anti-inflammatory
drug, a member of the class called nonsteroidal anti-inflammatory drugs,
or NSAIDs, which includes such common painkillers as Advil, Aleve, Celebrex
and Vioxx. If battling inflammation caused by immune cells helps one
type of learning and memory problem, she thought, maybe all these kids
needed was a dose of anti-inflammatory drugs to help their brains heal.
Environmental damage
The link between anti-inflammatory drugs and brain repair has to do
with how inflammation takes place. Immune cells rushing to damaged areas
release a soup of chemicals including IL-6. Some of these molecules recruit
nearby immune cells to join the attack, while others cause blood vessels
to leak fluid into the area. Within hours, the neighboring tissue begins
to swell, much as flesh puffs up around a splinter or other injury. These
chemical signals can help preserve tissue and clean up already damaged
cells, but they also change the neighboring cell’s environment — it’s
this environmental change that Monje suspected was behind the stem cell’s
reluctance to form new neurons.
Monje tested her idea both in a lab dish and in rats. First, she injected
a substance into rats that causes immune cells to become active and release
inflammation-causing molecules. The brains in these rats had far fewer
new neurons a week after the injection than the brains that had received
only water.
After this initial experiment, Monje gave some of the inflamed rats
twice-daily doses of the NSAID indomethacin. One week later, stem cells
in the rats were making neurons as regularly as in rats that had an injection
of only water.
These experiments pointed toward inflammation as the culprit behind
a stem cell’s reluctance to form neurons after radiation damage.
If this is the case, then giving rats an NSAID after radiation treatment
should block the inflammation and allow stem cells to develop into neurons.
Sure enough, when Monje exposed rats to radiation then gave them regular
doses of NSAIDs, they had significantly more new neurons in their hippocampus
two months later than rats that didn’t receive the NSAID.
Taken together, these results suggest that, at least in rats, chemicals
made by inflammatory cells prevent neuronal stem cells from repairing
damage in the hippocampus.
Halting those cells using NSAIDs seems to restore the brain to a more
hospitable environment.
Back to the bedside
Monje’s advisor, Palmer, says that while researchers in his lab
work out the role of inflammation in brain repair, he hopes to take the
research back where it began — to children who have had brain radiation
to treat cancer. He, Paul Fisher, MD, assistant professor of neurology
and neurological sciences, Michael Moseley, PhD, associate professor
of radiology, and John Desmond, MD, assistant professor of radiology,
hope that giving these children an anti-inflammatory along with radiation
treatment will allow their brains to recover.
Their first step is learning how to identify that damage on a brain
scan. They plan to start that this year, using functional MRIs to monitor
brain activity during a memory test in children who have had radiation.
If they can identify hallmarks of radiation-induced memory damage, they
will start giving the kids NSAIDS along with radiation treatment and
monitoring to see if their brains show fewer signs of damage.
If the trials are successful, Monje’s inspiration could eventually
help brain cancer patients emerge from radiation treatment with minds
equally prepared to take advantage of life’s chances. SM
Balming out brain disease: More
reasons to soothe an inflamed brain
Graduate student Michelle Monje’s work has inspired researchers
in her lab as well as a few others to investigate how inflammation affects
the brain. What they’ve found offers clues that could translate
into treatments for stroke, Parkinson’s disease and Alzheimer’s
disease.
Among the investigations:
• Benjamin Hoehn, an MD/PhD student working with neurosurgery
assistant professor Theo Palmer, PhD, and neurosurgery professor Gary
Steinberg, MD, is exploring whether blocking inflammation helps stem
cells mature into new neurons after a stroke. Past experiments have shown
that stem cells become active and begin producing new neurons soon after
a stroke, but those new neurons don’t survive. If his experiments,
using ibuprofen-like nonsteroidal anti-inflammatory drugs (called NSAIDs),
help those new neurons survive, NSAIDs could join the short list of treatment
options available for stroke.
• Tonya Bliss, PhD, a research associate working with Steinberg,
is discovering that inflammation in the brain isn’t all bad. She
says that although some inflammatory molecules prevent neural stem cells
from repairing brain damage, others beckon transplanted stem cells to
the injured site. “You’ve got good guys and bad guys and
it’s all a matter of working out which is which,” she says.
An eventual treatment could encourage the good guys to stay active while
thwarting the bad guys. In this scenario, a doctor could inject stem
cells into the outermost, most accessible, part of the brain and the
beckoning molecules would summon those cells to the correct location.
Once there, the cells could repair the damage in an environment free
of the inhibitory inflammation molecules.
• Brandi Ohmerad, PhD, a Michael J. Fox Foundation postdoctoral
scholar in the lab, has been sifting through molecules that instruct
stem cells in the hippocampus to divide and make neurons to see if the
cells are suppressed by inflammation. Ultimately, she hopes to fix the
environment so that stem cells can replace neurons even when inflammation
is present. She hopes this work will clarify whether inflammation interferes
with stem cells’ forming new neurons in the brain’s substantia
nigra, the region that degenerates in Parkinson’s disease. If it
does, reducing inflammation might encourage stem cells to develop into
neurons and help Parkinson’s patients, she says. Researchers at
the University of Basel, Switzerland, are doing similar research in Alzheimer’s
disease.
• Robin Price, an MD/PhD student in the lab, has been exploring
whether inflammation in pregnant rats alters how brain cells develop
in the offspring. He has found inflammatory molecules in the offspring’s
brains, but he’s still waiting to see whether that inflammation
changes how the brains develop.
So far, researchers have not proved their case against inflammation
in stroke, Parkinson’s disease or Alzheimer’s disease. But
signs point toward its eventual indictment in obstructing stem cells
from taking on the proper cell fate. What’s left is learning to
manipulate inflammation so it works for rather than against the body’s
repair system. — Amy Adams
Comments? Contact Stanford Medicine at
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