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BRAIN
COOLING AND GENE THERAPY MERGE TO OPEN STROKE TREATMENT WINDOW
SAN DIEGO—Cooling the brain and gene therapy techniques have significant therapeutic value individually, but now researchers have shown that the two therapies may yield even more benefits when they are combined. Together, the approaches work better to save neurons after a stroke as well as allow physicians more time to administer additional treatment, according to lead investigator Gary K. Steinberg, MD, PhD, and colleagues.
The researchers demonstrated that brief, mild postischemic hypothermia extended the therapeutic window for a specific type of gene therapy—Bcl-2—from 1.5 to five hours and that Bcl-2 plus hypothermia blocked cytochrome c release 48 hours after ischemia onset. “This is the first demonstration that postischemic hypothermia prolongs the time window for neuroprotection by gene therapy,” Dr. Steinberg and colleagues reported. “We now show that hypothermia extends the window for Bcl-2 gene therapy to five hours after ischemia onset.” Dr. Steinberg is a Professor of Neurosurgery at the Stanford University School of Medicine in California. He presented his findings at the American Stroke Association’s 29th International Stroke Conference. The complete results of the study were published in the February issue of Stroke.
A COOL IDEA
The concept of cooling the brain is not new, as Dr. Steinberg began experimenting with the procedure during brain surgery in 1991. For some types of surgeries, a brain that is 4°C cooler than normal is able to resist injury better than is a brain at normal body temperature. Previously, Dr. Steinberg and colleagues had shown that Bcl-2 overexpression with the use of herpes simplex viral vectors improved striatal neuron survival when delivered 1.5 hours after stroke but not when delivered five hours after stroke onset. The researchers theorized that chilling the brains might slow the release of cell-death molecules, allowing a longer window in which Bcl-2 treatment could be effective.
For their current work, Dr. Steinberg’s group cut off the blood supply to a portion of the brain in rats, thereby simulating a stroke. The rats were subjected to focal ischemia for one hour. Hypothermia (33°C) was induced two hours after insult and maintained for three hours. Five hours after ischemia onset, herpes simplex viral vectors expressing Bcl-2 plus ß-gal or ß-gal alone were injected into each striatum.
A CHILLING EFFECT
The researchers found that the number of surviving neurons was the same in all rats that had no gene therapy and in rats that had gene therapy without cooling. However, the rats in which the lowered body temperature was followed by gene therapy had two to three times more neurons that survived two days after the stroke.
In addition, double immunostaining of cytochrome c and ß-gal demonstrated that Bcl-2 plus hypothermia significantly reduced cytochrome c release. “These data demonstrate a synergistic effect of hypothermia and Bcl-2 overexpression, suggesting a potential clinical application of combined hypothermia and gene therapy,” the investigators reported.
Dr. Steinberg believes that if these findings can be replicated in humans, then chilling the brain may give physicians more time to treat patients who have had a stroke. This longer opening, he said, could make the difference in enabling patients to retain such functions as control of their limbs or the ability to speak normally after a stroke.
Dr. Steinberg also emphasized that Bcl-2 gene therapy is not yet an option for humans because the method used to insert the gene has not been perfected. Until then, he urged researchers to look for other treatments that may be possible to complete within the longer therapeutic window. These treatments include one of a wide range of proteins that, similar to Bcl-2, thwart the cell-suicide pathway and keep cells alive.
“Although intraischemic hypothermia provides long-term protection against cerebral ischemia, postischemic hypothermia may only transiently delay ischemic cell death unless protracted periods of hypothermia are used,” the investigators reported. “Neuroprotective agents may be coupled with short-term hypothermia to enhance its protective effects and to avoid the adverse effects of long-term hypothermia.”
The investigators are also studying the effects of hypothermia with other genes to extend the therapeutic window in treating patients with stroke.
Cooler
Heads Prevail—
Helmets
Aid Patients With Stroke |
| SAN
DIEGO—Two studies have demonstrated that a device
resembling an old-fashioned flight helmet can cool the brain without
significantly
affecting a patient’s core body temperature for hours, thus lengthening
the window to treat ischemic stroke. In results presented at the 29th
International Stroke Conference, one group of investigators tested a NASA-spinoff helmet on patients with severe hemispheric infarctions,
while another group used a helmet-type cooling apparatus on patients
with acute embolic stroke.
Huan Wang, MD, Assistant and Resident of Neurosurgery at the University
of Illinois, College of Medicine, in Peoria, and colleagues evaluated
six patients, average age 68, using a liquid cooling technology developed
by NASA scientist William Elkins. The researchers gauged brain temperature
via tiny fiberoptic probes inserted in the brain. The patients had neurologic
deterioration despite being treated for brain swelling. Dr. Wang and
colleagues measured patients’ brain temperatures before the subjects
wore the helmets and throughout the next 48 to 72 hours and found that
the helmet preferentially cooled the brain much more rapidly and profoundly
than it did the body. The patients’ brains cooled an average of
6°F the first hour, without dropping body temperature significantly.
The helmet continued cooling the brain while cooling body temperature
at a much slower rate.
The researchers were able to use the technology an average of six to
eight hours before body temperature dropped below 97°F. Five patients
tolerated the helmet cooling well. One 85-year-old woman with a previous
heart arrhythmia experienced an abnormal heart rate but responded promptly
to treatment.
“The goal with this therapy was to try to improve neurologic outcomes
by minimizing stroke’s effect,” said Dr. Wang. “The first
step in that direction was to find a therapy that effectively cooled
the brain and, judging by this study, we have.” Dr. Wang added that
because of its ease of application, the helmet can be used by emergency
management services personnel to treat patients with stroke in the field.
In the second study, Kentaro Yamada, MD, of the National Cardiovascular
Center in Osaka, Japan, and colleagues tested their cooling helmet on
patients, average age 68, three to 12 hours after stroke onset. The helmet
was attached to the patients’ head and neck, and cooling the head
continued nonstop for three to seven days without anesthesia.
The researchers evaluated functional outcome in patients three to 10
months after stroke. The surface cooling was performed successfully in
all patients. Tympanic temperature was lowered 4°F; jugular temperature
was lowered 1.4°F. In hypothermia with a helmet, such a temperature gradient
in the brain results because of the local nature of the cooling method,
said Dr. Yamada. Some patients experienced mild shivering, elevated potassium
levels, mild skin damage, and infections, but none had serious adverse
effects. After 10 months of follow-up, one patient had died. Six patients
had “good” functional outcome three to 10 months after stroke.
“Mild brain hypothermia can be achieved feasibly and safely by
the local surface cooling,” reported Dr. Yamada and colleagues. “While
neuroprotective effect of local cooling may be less powerful as compared
with that of systemic cooling, the local cooling may be clinically more
useful than the systemic cooling because of its safety and feasibility.” |
NR
—Colby Stong
Suggested Reading
Zhao H, Yenari MA, Sapolsky RM, Steinberg GK. Mild postischemic hypothermia prolongs the time window for gene therapy by inhibiting cytochrome c release. Stroke. 2004;35:572-577.
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