Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Steroids rapidly restore blood-brain barrier function after blast

12.03.2015

Columbia Engineering research findings could reduce mandatory rest periods for military personnel exposed to blast injury, enabling them to return to duty faster

Barclay Morrison III, associate professor of biomedical engineering at Columbia Engineering, has led the first study to determine underlying biological mechanisms that promote functional recovery of the blood-brain barrier (BBB) after blast injury. The research demonstrates that treatment with the glucocorticoid, dexamethasone, after primary blast injury promotes rapid recovery of an in vitro model of the BBB, a highly restrictive semi-permeable barrier whose primary function is to maintain the brain's microenvironment and protect it from potentially toxic substances. The study is published in the March 11 Advance Online Publication of the Journal of Cerebral Blood Flow & Metabolism.


This image shows increased tight junction immunostaining 1 day after blast injury due to dexamethasone (DEX) treatment. (A) Characteristic staining of the ZO-1 tight junction protein in untreated controls. (B) Reduced ZO-1 staining in untreated injured cultures after blast exposure. (C) Stronger ZO-1 tight junction staining in DEX-treated injured cultures. (D) Reduced ZO-1 staining in injured cultures treated with DEX and RU486 (mifepristone), inhibiting effects of DEX treatment alone.

Image courtesy of Barclay Morrison III/Columbia Engineering

"Our research should stimulate renewed clinical interest in developing glucocorticoid therapies to treat blast-induced traumatic brain injury (bTBI) and other disorders of the central nervous system," Morrison says. His findings also hold important implications for military personnel exposed to blast injury. "We may be able to improve outcomes in brain-injured soldiers and civilians," he continues, "and reduce the length of their mandatory rest periods before returning to duty, making the difference between requiring only days rather than weeks or longer to recover."

This improvement could be a significant result, as there are currently no approved pharmaceutical therapies for traumatic brain injury (TBI), and recently completed clinical trials have not demonstrated any benefit of other tested neuro-protective interventions. For patients with head injuries (non-blast related) and brain edema, doctors have been prescribing glucocorticoids, a class of steroid hormones, as standard treatment for the past 30 years. These drugs are also frequently used to manage central nervous system (CNS) disorders associated with a pathologically permeable BBB, such as with brain tumors and multiple sclerosis.

"But there have been mixed reports about the effectiveness of glucocorticoids after traumatic insult and their use in the clinic for TBI is controversial, partly due to side effects associated with high doses and long durations of treatment," Morrison notes. "Our study's positive results may lead the way to developing a more targeted therapy using steroids to quickly restore the integrity and function of the BBB after bTBI."

The U.S. Department of Defense has recorded more than 300,000 cases of TBI between 2000 and 2014, most caused by explosive blast. The prevalence of bTBI is largely due to the development of improved personal protective armor that has led to increased survival of military personnel who sustain injuries from blast. There are four types of blast trauma injury: 1) primary injury caused directly by the pressure wave, which can travel through tissue at velocities close to that of sound in water, 2) secondary injury caused by objects put in motion by the blast, 3) tertiary injury caused by an individual thrown into motion by the blast and hitting surrounding objects, and 4) quaternary injury caused by burns, explosion-related injuries, illnesses and diseases not attributed to the other three blast trauma types.

"Primary blast injury is a biomechanically distinct phase of bTBI that remains the least understood by researchers," explains Christopher Hue, Morrison's PhD student and lead author of the study. The shock wave that emanates from an explosion source as compressed and rapidly expanding gases can occur in milliseconds or less. Given the fine structure of the BBB--nearly every neuron has its own blood supply--primary blast can incur major damage. And damage to the BBB would allow potentially harmful blood constituents to flood the brain, and that, in turn, could wreak havoc on the neurons that make up the brain.

So, says Hue, "Speeding blood-brain barrier recovery is an important therapeutic target for developing new treatments for victims of bTBI."

Working in Morrison's Neurotrauma and Repair Laboratory at Columbia Engineering, the team developed a blast injury model using a shock tube and custom-designed sample receiver to simulate a primary blast event and applied it to an isolated, living model of the BBB that consisted of brain endothelial cells. The shock tube was designed to recapitulate blasts by generating shock waves with pressure histories similar to explosions from improvised explosive devices in open environments (i.e. a 105 mm mortar shell). They were able to test separate components of the central nervous system, including the BBB, in isolation, which gave them precise control over the mechanical "insult," and eliminated potentially confounding effects of inertial injury that are often present when studying the effects of blast in pre-clinical models.

"Our in vitro experimental strategy had a big advantage in that separate components of the CNS, including the BBB, can be tested in isolation from others," Morrison says. "We were the first to use our blast injury model to precisely control the biomechanical initiators of injury and measure subsequent changes to BBB function more directly than in vivo."

The study showed that treatment with dexamethasone resulted in full recovery of BBB function one day after injury, as opposed to three days in untreated samples. Morrison and his team are hoping next to translate their in vitro findings in vivo.

"The combination of in vitro and in vivo experimental models to understand the biophysical and molecular mechanisms of primary blast injury and the effects of treatment on the BBB offer a powerful set of tools to guide the development of novel therapeutic strategies to mitigate the consequences of bTBI," says Morrison. "Accelerating BBB recovery after blast exposure represents an important advance in addressing the multifaceted, short- and long-term complications associated with bTBI."

Hue adds, "We're especially excited about our results because our research may pave a way to help protect those men and women who put themselves in harm's way in the service of our country."

###

Morrison's injury model was developed in collaboration with Cameron R. Bass, associate research professor of biomedical engineering at Duke University, and David F. Meaney, Solomon R. Pollack Professor and chair of bioengineering at the University of Pennsylvania.

This research was funded by a Multidisciplinary University Research Initiative from the Army Research Office (W911MF-10-1-0526) and a National Science Foundation Graduate Research Fellowship (Christopher D. Hue; DGE-07-07425).

The authors declare that no competing financial interests exist.

Holly Evarts | EurekAlert!

More articles from Health and Medicine:

nachricht Why might reading make myopic?
18.07.2018 | Universitätsklinikum Tübingen

nachricht Unique brain 'fingerprint' can predict drug effectiveness
11.07.2018 | McGill University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Machine-learning predicted a superhard and high-energy-density tungsten nitride

18.07.2018 | Materials Sciences

NYSCF researchers develop novel bioengineering technique for personalized bone grafts

18.07.2018 | Life Sciences

Why might reading make myopic?

18.07.2018 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>