New Approach Counteracts Stroke's Inflammation Piece
BioWorld Today Science Editor
Genentech Inc.'s tissue plasminogen activator (tPA), the only FDA-approved stroke drug, works by getting rid of the blood clot that is blocking blood flow.
But getting rid of the clot is not the only possible way to deal with stroke.
Researchers at Stanford University identified a protein that appears to be able to mitigate the damage done by a stroke: the anti-inflammatory protein alpha-B-crystallin.
Unlike tPA, alpha-B-crystallin is "not a plumbing drug . . . it's a protection drug," co-corresponding author Larry Steinman told BioWorld Today.
TPA works by busting the clot, while alpha-B-crystallin works by counteracting its consequences.
As such, if alpha-B-crystallin pans out clinically, the two drugs could conceivably be synergistic in treating stroke.
And even if they are not, with 800,000 stroke patients a year in North America alone, Steinman said, there's "definitely room for more than one stroke drug."
Alpha-B-crystallin originally came to the attention of Steinman and his colleagues for its possible usefulness in multiple sclerosis. (See BioWorld Today, Aug. 14, 2007.)
Since that time, Steinman said, "we've taken [alpha-B-crystallin] into a number of animal models," including heart attacks, retinal ischemia and rheumatoid arthritis" – and into stroke.
That may seem strange at first, since on the face of it, stroke is not an inflammatory disease. But, Steinman said, "there is a large inflammatory response to oxygen deprivation . . . any attempt at inhibiting the influx of inflammatory cells may be beneficial in stroke."
Also, atherosclerosis, which is at the root of strokes, "does have a big immune-inflammatory component," Steinman said, and the possibility of using immune-depressing drugs in stroke has received "a lot of attention."
Stroke damage comes via "multiple mechanisms," co-corresponding author Gary Steinberg elaborated. First, the lack of blood flow, and the oxygen and nutrients it contains, to the brain kills some cells. Some damage is done via oxidative stress due to reperfusion injury, which occurs when blood flow to formerly starved areas is restored. So-called excitotoxic damage is done by the excessive release of calcium and glutamate.
And finally, Steinberg told BioWorld Today, "all this attracts inflammatory cells. And though they are supposed to be cleaning up the damage, they do some damage as well."
In their current studies, which were published in the July 25, 2011, advance online edition of the Proceedings of the National Academy of Sciences, the authors found that alpha-B-crystallin knockout mice had more damage after a stroke than their wild-type cousins.
Administering alpha-B-crystallin after a stroke reduced the volume of brain tissue that was damaged by the stroke. It did so by decreasing and counteracting the inflammatory chemicals that are given off, and increasing antiinflammatory chemicals. Both effects cooperate to blunt inflammation.
Bone marrow cross-transplant experiments between normal and knockout animals revealed that the protein has effects both in the brain, and in the periphery – "that may be why it is so potent," Steinberg said.
A potential strength of alpha-B-crystallin is that it could be effective in both hemorrhagic and ischemic stroke; tPA is useful only in ischemic stroke and can worsen the damage done by hemorrhagic stroke, which further intensifies the race against the clock that its 4.5 hour post-stroke time window of effectiveness dictates.
Alpha-B-crystallin may also have a longer time window than tPA. In the team's animal studies, administering alpha-B-crystallin helped for up to 12 hours after a stroke, a finding which Steinman called "very exciting" – and which, Steinberg pointed out, may not be the end of the road: 12 hours is as far out as the team has looked to date, and it is possible that alpha-B-crystallin might still be effective after even longer time periods.
How directly the 12-hour window would translate is unclear, though. Both Steinberg and Steinman were optimistic but well aware of the limits of mouse models: "We've done about as well as we can do in this animal model," Steinman said.
What's needed next, he added, is a proof-of-concept study in the clinic: "a small trial in a short amount of time spending reasonable amounts of money."
Stanford University has spun out a start-up based mainly on the multiple sclerosis findings.
That company, Cardinal Therapeutics Inc., is about 3 years old, has some angel and seed funding and "is out there on the road looking for partnerships in this tough environment."
Published: July 26, 2011
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