It’s estimated that five million people in the U.S. suffer from the long-term effects of traumatic brain injury (TBI)—which can range from coma to loss of movement to cognitive and behavioral problems. A large percentage of soldiers injured in Iraq and Afghanistan have sustained some form of TBI. Scientists have been searching for years for drugs that could ameliorate the effects of these injuries, but so far, none have been shown to prevent damage or speed healing.
Researchers at Wayne State University in Detroit are investigating a drug that they hope could prevent the damage of TBI by improving blood flow to the brain. So far, the drug, called clazosentan, has shown promise in animal tests in improving recovery after a blow to the head.
Christian Kreipke, the lead author of a study describing the tests, says that most experimental TBI treatments have targeted two problems in the injured brain: dangerous swelling of the brain, and structural damage to neurons.
In contrast, his team is trying to prevent a third side effect of injury: a narrowing of blood vessels, which can restrict blood flow to brain tissue. Kreipke says that after an injury, the brain’s blood vessels enter a cycle of narrowing and dilating that eventually leads to a condition called vasospasm, in which blood vessels constrict and cut off flow to the brain. Vasospasm is a frequent occurrence in brain injuries, and particularly common in soldiers with TBIs caused by blasts.
In a study published last year in Neurological Research, his team showed that administering the drug 30 minutes after a brain trauma could reduce the amount of injury to brain cells in rats; animals treated with the drug also showed more improvement in a maze test than untreated brain-injured rats. This April at the American Academy of Neurology’s annual meeting in New Orleans, the team will present further data showing that the drug can have beneficial effects in rats when administered up to 12 hours after injury, which Kreipke compares to a day after injury in humans. This relatively long window of opportunity could be important, Kreipke says, for injury victims like soldiers who can’t access immediate treatment, or patients who don’t realize the extent of their injury immediately.
Kreipke says that previous drugs to target blood vessel constriction have caused the vessels to dilate too much, which can put a patient at risk of bleeding. Clazosentan, he says, has a more specific action—it blocks a receptor in cells called endothelin receptor A, which is involved in vessel constriction. “This drug doesn’t cause more blood flow,” he says—it just decreases the severity of the drop in flow.
Ross Zafonte, a TBI expert at Spauding Rehabilitation Hospital in Boston, says the concept of targeting blood flow abnormalities in TBI is promising, and adds that this drug, with its specific molecular target, is a “more refined and elegant variant” on this strategy. But he cautions that many TBI treatments developed over the years “have looked good in the laboratory,” including in rodent tests, “yet very few things have been shown to be helpful in humans.”
Clazosentan, which is manufactured by Swiss company Actelion Pharmaceuticals, has recently been investigated as a treatment for brain hemorrhage, but clinical trial results have been disappointing. Kreipke has higher hopes for its efficacy in TBI. Because the drug has already been through safety testing in humans, he hopes to move ahead soon with a clinical trial for patients with moderate to severe TBI.
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