ByGwyneth Dickey Zakaib of Nature magazine
it Parker doesn't just study traumatic brain injury in the lab, he's also seen it at close range while serving in Afghanistan. He has since made it his mission to untangle the mechanisms that underlie the brain's response to jarring injuries, which often result from proximity to an explosion.
After the initial impact, the connections between nerve cells in the brain retract and sometimes the blood vessels constrict (vasospasm). Research by Parker, a bioengineer at Harvard University in Cambridge, Massachusetts, and his colleagues suggests that a signalling pathway involved in cell contraction -- the Rho-ROCK pathway -- is responsible for both of these effects.
Their findings are reported in two papers, one published today byPLoS ONE and the other last week in Proceedings of the National Academy of Sciences.
Although Parker doesn't have a neuroscience background, as a postdoc he worked with integrins -- membrane-spanning proteins that attach a cell's inner structure, or cytoskeleton, to an outer matrix. He knew that integrin stimulation sets off signalling cascades, including one that brings about cell contraction. The vasospasm associated with soldiers' traumatic brain injury (TBI) led him to propose a role for integrins, and he predicted that the same pathway could also cause neuronal extensions, or axons, to contract.
So he and his team created devices to abruptly stretch engineered human blood vessel tissue and rat neurons in a way that might mimic blast waves travelling through the brain. The treatment caused neuronal extensions to swell, a sign that they would soon retract. Stretching also made blood vessel tissue more sensitive to a cell protein that causes constriction. Meanwhile, when the researchers applied a Rho-ROCK pathway inhibitor, injury to neurons and blood vessel tissue was either delayed or prevented.
Parker thinks that rapid stretching of blood vessels or neurons "plucks" the integrins with more force than they are designed to handle. This overstimulates the Rho-ROCK pathway, causing axons to withdraw and blood vessels to constrict.
"This is pathological activation of a totally healthy signalling pathway," says Parker. And because the same pathway is involved in both blood vessels and neurons, one drug could address both problems. "That's a really a rich therapeutic opportunity."
Parker adds, however, that there is still a long way to go before the finding could translate into preventative treatments. He'll need to make his cell models more complex, to explore the roles of other pathways, before testing can begin on animals or humans. He also wants to try to mimic smaller forces with his tests -- a football tackle, for instance -- to see whether the same mechanism comes into play.
"It's an elegant demonstration that biomechanical stretch will produce changes in the cytoskeleton," says David Hovda, director of the Brain Injury Research Center at the University of California, Los Angeles. Although he can't be sure that the models Parker's group used represent exactly what goes on in the brain during a blast, he says, "this is an important fundamental discovery".
Ken Barbee, a bioengineer at Drexel University in Philadelphia, Pennsylvania, says that the papers have caught his attention, but he's not convinced that the Rho-ROCK pathway is the primary mechanism responsible for TBI. He has linked neuronal membrane tears with a form of TBI, and successfully mitigated cell destructionin vitro with a drug that repairs them.
Harvard graduate student Borna Dabiri, a co-author on both papers, agrees. Membrane tears do occur, but probably at higher strains than those he and his colleagues exerted in their experiments, he says, and it's not clear exactly what happens in the brain on impact. "Which mode dominates might depend on the severity of the injury," he says."I think the reality is that when the whole tissue undergoes deformation, you're probably going to get a combination" of of neuronal injuries and biological pathways, Barbee says.
Parker has plenty of motivation to continue on the road towards a definitive answer. His time in Afghanistan, says the US Army major, makes this "a very serious and personal endeavour". "These are my brothers that are over there getting blown up."
This article is reproduced with permission from the magazine Nature. The article was first published on July 22, 2011.