Scientists discover potential stroke treatment that may
extend time to prevent brain damage
BY BRUCE GOLDMAN
A naturally occurring substance shrank the size of stroke-induced lesions in
the brains of experimental mice — even when administered as much as 12 hours
after the event, Stanford University School
of Medicine researchers have shown. The substance, alpha-B-crystallin, acts
as a brake on the immune system, lowering levels of inflammatory molecules whose
actions are responsible for substantial brain damage above and beyond that
caused by the initial oxygen deprivation of a stroke.
The finding, published online July 25 in Proceedings of the National
Academy of Sciences, is of great potential significance. Every year brings
nearly 800,000 new stroke patients in North America. “That’s one every 40
seconds,” said Gary
Steinberg, MD, PhD, director of Stanford’s Institute for Neuro-Innovation and
Translational Neurosciences and one of the study’s two senior authors.
Steinberg is also the Bernard and Ronni Lacroute-William Randolph Hearst
Professor of Neurosurgery and the Neurosciences, and chair of neurosurgery at
the medical school.
The largest single cause of severe neurological disability and the
third-leading cause of death in the United States, stroke accounts for an
estimated $74 billion annually in related costs, including treatment and
additional assistance for the three of every four stroke patients whose ability
to perform the activities of daily life is impaired. Strokes are caused by a
sudden drop in the flow of blood to the brain resulting from a clot or, less
often, bleeding. One of every three stroke patients is under the age of 65. In
all, there are 5.4 million stroke survivors in the United States and 15 million
The only currently approved drug for stroke — tissue plasminogen activator,
or tPA — dissolves clots that keep oxygenated blood from reaching brain tissue.
To be effective, tPA must be administered within about 4.5 hours after the
stroke. But patients’ brains must first be scanned to rule out the possibility
that the stroke was caused by bleeding, which tPA would exacerbate, rather than
Moreover, tPA does nothing to counter the stroke’s insidious inflammatory
aftershock: a flood of noxious chemicals secreted by angry immune cells that
rush in to the affected area, causing significant further damage.
Alpha-B-crystallin appears to act as a sponge, sopping up those bad actors
and stopping inflammation from making a bad situation worse.
Alpha-B-crystallin is a major structural protein in the eye’s lens. It is
also constantly made in the heart. In other tissues, including the brain, its
production can be triggered by stressful events, such as oxygen deprivation or
excessive heat or cold. Growing evidence suggests that alpha-B-crystallin can
help curb inflammatory activity in the brain.
“The brain doesn’t roll over and play dead when it’s under attack,” said Lawrence
Steinman, MD, the other senior author of the new study, who is the George A.
Zimmermann Professor of Neurology and Neurological Sciences and Pediatrics as
well as chair of Stanford’s interdepartmental program in immunology.
In an earlier study, published in Nature in 2007, Steinman and his colleagues
found that the presence of alpha-B-crystallin could help reduce the severity of
brain damage caused by multiple sclerosis, a chronic, debilitating autoimmune
disease of the brain. Other studies published this year by his group have shown
that alpha-B-crystallin limits the damage caused by blood-supply cutoffs to
heart tissue and the retina.
It seemed logical to see if this protein could mitigate the effects of a
stroke. “We made a jump from its relevance in inflammatory diseases such as
multiple sclerosis,” Steinberg said. “To my knowledge, nobody had looked at
concentrations of alpha-B-crystallin after a stroke, either in people or in an
experimental animal model before.”
So, along with first authors Ahmet Arac, MD, a postdoctoral scholar in
Steinberg’s lab, and Steinman’s former graduate student Sarah Brownell, PhD,
Steinberg and Steinman turned to a standard animal model: the laboratory mouse.
They found that, in mice bioengineered to lack alpha-B-crystallin,
experimentally induced stroke lesions were more massive than those induced in
otherwise genetically similar mice whose cells were capable of making the
protein. The alpha-B-crystallin-deficient mice had worse neurological function
after the stroke than did the normal mice.
The researchers also found that supplying synthetic alpha-B-crystallin to the
deficient mice reduced brain-lesion sizes after a stroke, even when the
substance was administered 12 hours after the stroke was induced. And they saw
elevated alpha-B-crystallin levels in blood plasma from both human patients and
mice after a stroke. (The human samples were obtained from study co-author Gregory Albers, MD,
the Coy Foundation Professor of Neurology and Neurological Sciences and the
director of the Stanford Stroke
“In younger patients, the larger the stroke, the higher the concentration of
alpha-B-crystallin,” said Steinberg. Interestingly, increased alpha-B-crystallin
levels were not detected in plasma from patients over the age of 80, whose
strokes typically have worse consequences than those affecting younger
Finally, the investigators demonstrated that alpha-B-crystallin-treated mice
produce fewer inflammatory immune-signaling molecules and more anti-inflammatory
ones than untreated mice.
At the doses given to the mice in this study, alpha-B-crystallin appeared to
be nontoxic. “This is a naturally occurring molecule the body is already
producing, although maybe just not enough of it,” said Steinberg. “We’re just
supplementing it.” If further studies by other labs and in other models confirm
and extend the findings, alpha-B-crystallin may be an excellent candidate for
clinical trials in stroke, Steinman and Steinberg both said.
“This is the first demonstration of an efficacious brain-protecting agent
that targets the inflammatory aspect of stroke in a novel way, and it can be
given at quite a delay,” said Thomas Carmichael, MD, PhD, professor and vice
chair of neurology at the David Geffen School of Medicine at UCLA. Carmichael, a
stroke expert, did not participate in the study but is familiar with its
methodology and results. “Tissue plasminogen activator has a fairly narrow
risk-to-benefit ratio. The longer you wait, the more likely it is to stimulate a
Other Stanford co-authors were Jonathan Rothbard, PhD, a senior research
associate in Steinman’s lab; Charlene Chen, MD, a fellow at the Stanford Stroke
Center; and postdoctoral scholars Rose Ko, PhD, and Marta Pereira, PhD. The
study was sponsored by the Russell and Elizabeth Siegelman, Bernard and Ronni
Lacroute and William Randolph Hearst foundations; the National Multiple
Sclerosis Society; and the National Institutes of Health.
Information about Stanford’s departments of Neurology and Neurological
Sciences and of Neurosurgery, which also supported the research, is available at