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Stanford Report, November 17, 1999

$4.7 million grant sparks stroke research collaboration

BY KRISTA CONGER

Many people might dismiss dizziness, weakness, blurred vision and loss of muscle coordination as simply the result of increasing age or fatigue. But these symptoms, as well as a sudden, severe headache, one-sided numbness and difficulty speaking or understanding simple statements may signal a new or recurring stroke -- a medical emergency that strikes more than three-quarters of a million Americans each year.

Prompt treatment is vital to preventing drastic consequences; strokes are the leading cause of disability and the third most common cause of death in the United States.

Now Stanford researchers from several departments have joined forces to devise new treatments to prevent the cellular mayhem that causes stroke symptoms. The Center for Cerebrovascular Disease, established with a $4.7 million grant from the National Institute of Neurologic Disease and Stroke, will consolidate the efforts of scientists from the departments of neurosurgery, neurology and neurological sciences, biological sciences and anesthesia in the ambitious five-year effort. The researchers hope to identify protective agents that can minimize the damage done to neurons in the brain during a stroke.

"Having us all work together and exchange ideas is a distinct advantage," said Gary Steinberg, MD, PhD. Steinberg is a professor and chair of the Department of Neurosurgery and scientific director of the new program project grant. "It's really a nice example of a collaborative effort utilizing the talent we have at Stanford in different departments."

That talent will be focused on preventing the neuronal cell death that is the hallmark of stroke. The damage is done when blood vessels in the brain are blocked or suddenly rupture, depriving areas of the brain of oxygen. As oxygen-starved cells begin to die, they release toxic chemicals -- free radicals -- that damage or kill surrounding cells and tissues in a domino effect. The cellular carnage can continue for several hours or days after the initial event, leaving the patient with irreversible neurological damage.

Participants in the Center for Cerebrovascular Disease want to throw a wrench into this cycle of destruction by identifying genes that might protect neurons in this punishing environment. If researchers can find a way to prompt these genes to turn themselves on after a stroke, or administer a modified virus to express these genes within the brain, some of the neurons might be kept alive and functioning, they theorize. But because the genes protect against -- but don't repair -- cellular damage, any such treatment is a race against the clock.

"We may have a three- to four-day window for some types of stroke," said Steinberg. "For other types we may have only three to six hours to begin treatment."

During this time, neurons in the stroke-affected region can die in two ways. A lack of oxygen can cause the energy-generating machinery in the affected cells to grind to a halt, releasing toxic chemicals that can kill other cells and lead to a localized region of tissue death, a process called necrosis. Alternatively, a cell damaged by rampaging free radicals released by its dying neighbors can initiate a suicide program known as apoptosis.

In order to develop stroke treatments that can interfere with either type of cell death, the researchers are tackling the problem with a three-pronged approach, studying individual cells in culture as well as normal and genetically modified rodents. In each model system, scientists are investigating the effect of three classes of genes known to play a role in deciding how and when cells die.

Hsp70 is a protein produced in cells in response to stressful conditions, such as higher than normal temperatures or lack of oxygen. Excess production of hsp proteins in normal rats has previously been shown by Steinberg's group to protect neurons before a stroke is induced.

Steinberg's lab, together with the laboratories of Robert Sapolsky, PhD, professor of biological sciences and Midori Yenari, MD, assistant professor of neurosurgery and of neurology and neurological sciences, is studying the proto-oncogene bcl-2. Bcl-2 has been implicated in both the apoptotic and necrotic pathways of cell death. Recently the scientists have identified a neuroprotective effect of bcl-2 when administered even after a stroke has been induced.

"With the most common type of stroke we are able to protect by injecting [bcl-2] an hour and half after the insult," said Steinberg of the rodent experiments. This is potentially good news for human stroke sufferers, whose condition strikes without warning.

In addition to hsp70 and bcl-2, Stanford researchers will study another class of genes for potential neuroprotective effects. The anti-oxidant enzymes SOD1, SOD2 and GSPx scavenge the free radicals that can damage surrounding cells, possibly preventing the cascade of death leading to neurological impairment.

While Steinberg's laboratory will collaborate with Yenari's group to further investigate the effect of inducing the expression of these genes in normal rats, the laboratory of Pak Chan, PhD, professor of neurosurgery, will generate genetically modified animals that over-express the genes in question.

The laboratory of Rona Giffard, MD, PhD, associate professor of anesthesia, rounds out the center's team of cerebrovascular disease experts. Together with the Sapolsky group, Giffard's laboratory will test the effect of the genes at the level of an individual cell in culture. This approach eliminates many of the complexities encountered when studying whole animals, and allows greater understanding of what occurs at the molecular level during times of oxygen deprivation.

"It's really unique," said Steinberg of the collaborative approach stimulated by the grant. "This is a program project that incorporates people from five different labs and four different departments." But departmental differences aside, all of the researchers hope that their molecular focus will increase understanding of the pathophysiology of stroke and help pinpoint which of these genes holds the most promise as a therapy for stroke sufferers. SR