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Scientists discover potential stroke treatment that may extend time to prevent brain damage

STANFORD, Calif. — 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 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 by blockage.

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.

"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."

A naturally occurring substance which slows the immune system could be used to reduce the swelling after stroke which adds to the initial damage caused to the brain by oxygen deprivation.

A study on mice showed that a protein known as alpha-B-crystallin, which is naturally produced in response to stress, can work like a sponge to soak up inflammatory molecules in the brain and reduce further damage.
Stroke, the third most common cause of death in Britain, happens when blood flow to the brain suddenly drops due to a clot or bleeding.
Mice which were genetically engineered to lack alpha-B-crystallin suffered more brain damage from stroke than normal mice in an experiment by Stanford University scientists.

Like a runaway truck careening down a mountain and then having the brakes fall off, the immune attack against alphaB-crystallin worsens the situation," says Lawrence Steinman, M.D., professor of neurology and neurological sciences. And remarkably, he notes, addition of that protein works like restoring the failing brakes, returning control.

What is interesting to note is that Steinman and his Stanford team are finding the same immune system reaction against alphaB-crystallin in stroke....not just MS.

The recognition of this protein's role in multiple sclerosis began more than a decade ago, when Dutch researcher Johannes Van Noort, PhD, found that the main stimulant of the immune system's attack on the brain was not the presumed culprit of one of the parts of myelin, but alphaB-crystallin, the major structural protein of the lens of the eye.

"For some reason, the protein gets turned on in the brain where it's not expected to be,"

Hypoxic stress results in increased expression of vascular endothelial growth factor (VEGF), a known stimulator of angiogenesis. Increases in expression result in both properly folded and misfolded VEGF proteins. Misfolded VEGF is exported from the endoplasmic reticulum (ER) into the cytoplasm and ubiquitinated. (A) Hypoxic stress also stimulates phosphorylation of αB-crystallin (αB). Phosphorylated αB-crystallin binds misfolded, monoubiquitinated VEGF and returns it to the ER, where it is folded correctly and transported to the Golgi apparatus for secretion. Thus, the secretion of VEGF is up-regulated, angiogenesis occurs, and hypoxic stress may be reduced. (B) Properly folded VEGF is still transported to the Golgi and secreted. In the absence of αB-crystallin, misfolded, monoubiquitinated VEGF accumulates in the cytoplasm. Some of this will become polyubiquitinated and degrade. The rest of the misfolded VEGF can aggregate, leading to increased stress on the cell. Because misfolded VEGF cannot be transported back to the ER to be refolded, decreased secretion of VEGF occurs and hypoxic stress continues.

The association of a B-crystallin (heat shock protein [Hsp] B5) with multiple sclerosis (MS) has been a puzzling story (1). Van Noort and colleagues (2, 3) first proposed the protein to be an autoantigen in 1995 based on the reactivity of PBMCs from MS patients and healthy control subjects to pro- liferate in response to a fraction of myelin from MS brains containing a B-crystallin