Brain Damage From Stroke Reduced With Natural Protein Given Up To 12 Hours Later
The protein slows down the immune system by lowering levels of molecules that can damage the brain more than the initial damage caused by the oxygen starvation of a stroke.
Stroke is the leading cause of neurological disability and the third biggest killer in the US, where there are 800,000 new stroke patients every year, "that's one every 40 seconds," said co-senior author Dr Gary Steinberg, director of Stanford's Institute for Neuro-Innovation and Translational Neurosciences.
Stroke occurs when a part of the brain suddenly loses its blood supply, usually because of a blood clot, or more rarely, because of bleeding. One third of stroke patients are under the age of 65.
In the US, there is one approved drug for treating stroke, tissue plasminogen activator, or tPA. This dissolves clots that are stopping the affected part of the brain from getting oxygen-rich blood. However, it works best when given within 4.5 hours of the stroke, and only then if the patient first has a brain scan to rule out bleeding as the cause of the stroke, or giving them tPA could make things worse.
Also, tPA does nothing to reduce the immune response that sends inflammatory molecules to the affected area, causing further damage.
Alpha-B-crystallin is naturally occuring in the body: it is constantly being made in the heart and it is a major protein that helps maintain structure in the lens of the eye. It is also a stress-response chemical, released by tissues in response to extreme temperatures or oxygen starvation. It appears to behave like a sponge, mopping up molecules that increase inflammation.
From observing this habit in other conditions and diseases like multiple sclerosis, Steinberg and colleagues had a hunch that the protein might help minimize tissue damage after strokes.
"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," said Steinberg.
For their study, the researchers induced stroke lesions in mice bred to lack the ability to make alpha-B-crystallin and found they were much bigger than those induced in genetically similar mice that did not lack the ability to make the protein. Also, the protein-deficient mice had worse neurological function after the stroke than their non-deficient counterparts.
Then, when the researchers gave the protein-deficient mice the protein, they found their brain lesions shrank, even if they were treated 12 hours after the stroke event.
They also observed that human patients, as well as normal mice, have higher levels of alpha-B-crystallin in their blood after a stroke.
"In younger patients, the larger the stroke, the higher the concentration of alpha-B-crystallin."
And it was interesting that they did not find higher levels in patients over 80. Strokes in this age group tend to do more damage.
The researchers found that mice treated with the protein also produced higher levels of anti-inflammatory molecules and fewer inflammatory-signaling molecules than their untreated counterparts.
Steinberg said the protein occurs naturally in the body, but perhaps we don't make enough of it, and treatment could be just a matter of "supplementing it".
The researchers now hope other labs can replicate their findings so that the protein can move to the next stage and be trialled as a potential stroke treatment.
Dr Thomas Carmichael, professor and vice chair of neurology at the David Geffen School of Medicine at UCLA was not involved with the study. However, he is a stroke expert and understands how Steinberg and colleagues went about their research. He told the press that:
"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."
"Tissue plasminogen activator has a fairly narrow risk-to-benefit ratio. The longer you wait, the more likely it is to stimulate a hemorrhage," he added.
"Systemic augmentation of [alpha]B-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation."
Ahmet Arac, Sara E. Brownell, Jonathan B. Rothbard, Charlene Chen, Rose M. Ko, Marta P. Pereira, Gregory W. Albers, Lawrence Steinman, and Gary K. Steinberg.
PNAS, published ahead of print 26 July 2011, doi:10.1073/pnas.1107368108
Link to Abstract.
Additional sources: Stanford University School of Medicine.
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