Heat shock protein shields
against strokes, seizures
BY WILLIAM A. WELLS
A protein made in times of
cellular stress can protect the brain from damage induced
by a stroke or seizure, Stanford researchers have
demonstrated in gene-transfer experiments with rats. The
finding might eventually translate into a useful medical
treatment, they suggest.
The protein, heat shock
protein 72 (HSP72), is produced by cells that are
stressed by heat, chemicals or lack of nutrients. The
scientists found that a modified herpes virus that makes
the protein reduced nerve cell death when injected into
rat brains.
"This is the first
demonstration that gene transfer with this particular
protein can protect the brain against injury in animal
models," said Gary Steinberg, MD, PhD, professor of
neurosurgery and co-director of the Stanford Stroke
Center. Steinberg is the senior author of the study,
reported in the October issue of Annals of Neurology.
The researchers mimicked a
stroke in rats by blocking blood flow to part of the
brain. This reliably damaged the striatum, a region deep
in the brain. Injection of the virus that makes HSP72
increased survival of nerve cells in the striatum from 62
percent in untreated rats to 95 percent in the treated
ones, the researchers found.
To model damage caused by
seizures, they added a chemical called kainic acid, which
overstimulates the brain. A brain region called the
hippocampus is particularly hard hit by kainic acid. In
this region, the team found that nerve cell survival
increased from 22 percent to 64 percent when extra HSP72
was present.
Although the work is a
promising advance, Steinberg emphasized that translating
the new findings into a practical treatment for stroke
and other forms of brain damage will require a more
efficient way to deliver the protein. In their study, the
researchers had to deliver the virus by injection into
the brain, and the virus did not spread far beyond the
injection site.
But the current work does
strengthen the scientific rationale for pursuing a
treatment based on HSP72, he said. "Heat shock
proteins are induced in stroke, but until now, no one
knew what that meant whether these proteins were just
markers of cell death or if they were actually
protective," Steinberg explained. "This is one
of the first studies showing that producing extra heat
shock protein causes protection."
Strokes start when wayward
blood clots block a blood vessel, cutting off the supply
of oxygen and nutrients to part of the brain. Without
these energy sources, the nerve cells in that area
release toxic chemicals, including oxygen radicals and
excitatory amino acids. Eventually these nerve cells die.
Brain seizures start similar cascades of cell death,
Steinberg said.
Exactly how HSP72
intervenes in this process is not clear. In other cells,
however, heat shock proteins are known to recognize and
fasten onto damaged proteins, either helping the proteins
to reshape themselves or escorting them to their
destruction. Either action could help keep nerve cells
alive.
Steinberg and his
colleagues injected the HSP72-producing virus 12 hours
before blocking a blood vessel or adding kainic acid.
Such a preemptive procedure clearly is not possible for
most real strokes, although it might prove useful in
situations where a patient is known to be at high risk of
brain damage, Steinberg said. Brain surgery or
cardiovascular surgery, for example, can sometimes lead
to blockage of blood vessels, either deliberately by the
surgeon or inadvertently by a clot that has been
dislodged.
To see whether a treatment
could ever be developed for the more common,
unpredictable form of stroke, Steinberg and his
colleagues will now test whether injecting the virus
after brain injury can help.
Similar experiments with
Bcl2 a protein that turns off the cell's suicide
mechanism have proved successful. In these earlier
studies, Steinberg and collaborator Robert Sapolsky, PhD,
professor of biological sciences, found that injecting
the virus that makes Bcl2 can reduce nerve cell death
even when the virus is given hours after the brain
injury.
Steinberg's colleagues on
the newly published study were Sapolsky, assistant
professor of neurology Midori Yenari, MD, neuroscientist
and postdoctoral student Sheri Fink, PhD, research
assistant Guo Hua Sun, MD, PhD, graduate student Louis
Chang, undergraduate student Maitraya Patel, senior
research assistant David Kunis, research assistant David
Onley and senior research scientist Dora Ho, PhD.
Funding came from the
National Institute of Neurological Disorders and Stroke,
the National Institute for General Medical Sciences, the
Howard Hughes Foundation, the Adler Foundation, and
Bernard and Ronni Lacroute. SR
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