July 25, 2011

TBI in Wounded Vets: New Findings

(Ivanhoe Newswire) "“ New findings offer new hope for the treatment of traumatic brain injury (TBI) in veterans wounded by explosions. Researchers have identified for the first time, the mechanism for diffuse axonal injury and explained why cerebral vasospasm is more common in blast-induced brain injuries than in brain injuries typically suffered by civilians.

"These results have been a long time coming. So many young men and women are returning from military service with brain injuries, and we just don't know how to help them," Kevin Kit Parker, principal investigator, a professor of Bioengineering at Harvard's School of Engineering and Applied Sciences, and a major in the U.S. Army, was quoted saying.

When the brain encounters a loud force, such as an exploding roadside bomb, the delicate tissue slams against the skull, and results can be a temporary concussion, a more dangerous hemorrhage, or long-term TBI, which can even lead to the early onset of Parkinson's or Alzheimer's diseases.

Using cutting-edge tissue engineering techniques"”essentially creating a living brain on a chip"”biologists, physicists, engineers, and materials scientists have collaborated to study brain injury and potential targets for treatment. Researchers in his group have identified the cellular mechanism that initiates diffuse axonal injury, offering urgently needed direction for research in therapeutic treatments.

Their studies show that integrins, receptor proteins embedded in the cell membrane, provide the crucial link between external forces and internal physiological changes. Integrins connect the structural components within the cell with the extracellular matrix that binds cells together into tissue. Collectively, this network of structural and signaling components is referred to as the focal adhesion complex. The research has confirmed that the forces unleashed by an explosion physically disrupt the structure of the focal adhesion complex, setting off a chain reaction of destructive molecular signals within the nerve cells of the brain.

Inside the neuron, integrins normally mediate the activation of the proteins RhoA and Rho kinase (ROCK). When the focal adhesion complex is disturbed, the Rho-ROCK signaling pathway goes haywire; it directs the motor protein actin to retract the cell's arm-like axons, disconnecting the neurons from each other and collapsing the cellular networks that constitute the brain.

"Our research has shown that abrupt mechanical forces, such as those from a blast wave and transduced by integrins, can result in neural injury," Matthew A. Hemphill, one of the lead authors of the paper in PLoS One, was quoted saying.

"We also found that treating the neural tissue with HA-1077, which is a ROCK inhibitor, within the first 10 minutes of injury, reduced the number of focal swellings. We think that further study of ROCK inhibition could lead to viable treatments within the near future," Borna Dabiri, another lead author, was quoted saying.

The team also solved another mystery in TBI, explaining why cerebral vasospasm, a dangerous remodeling of the brain's blood vessels, occurs more commonly in TBI caused by explosions than in other types of brain trauma. "Until now, other researchers looking at TBI focused on ion channels and membrane poration, and it was generally accepted that cerebral vasospasm was only caused by hemorrhaging. It turns out that it's much more complicated than that," Patrick W. Alford, a former postdoctoral fellow in Parker's lab and lead author of the paper in PNAS, was quoted saying. "Integrins and Rho-ROCK signaling appear to be players in both diffuse axonal injury and cerebral vasospasm," Alford said.

The blast from an explosion creates a surge in blood pressure, which stretches the walls of the blood vessels in the brain. The team built artificial arteries, made of living vascular cells, and used a specialized machine to rapidly stretch them, simulating an explosion. While this stretching did not overtly damage the cellular structure, it did cause an immediate hypersensitivity to the protein endothelin-1. Endothelin-1 is known to stimulate vascular cells to absorb calcium ions, which affect actin"”the same protein involved in the retraction of axons.

In the 24 hours following the simulated blast, the vascular tissues hypercontract and undergo a complete phenotypic switch, disrupting the overall function of the tissue. Both of these behaviors are characteristic of cerebral vasospasm. Most importantly, as in the neural tissue, the Rho-ROCK signaling pathway plays an important role in the behavior of actin and the cells' contraction. Parker's team found that inhibition of Rho soon after the injury can mitigate the harmful effects of the blast on the brain's vascular system.

"We have established a toe-hold as we try to climb up on top of this problem. In many ways, this work is just the beginning," Parker said.

SOURCE: Proceedings of the National Academy of Sciences and PLoS, July, 22, 2011