Researchers prevent post-traumatic brain damage using experimental drug

In animal studies, researchers from Georgetown University Medical Center have shown how traumatic brain injury leads to loss of brain function - and found that an experimental drug can stop the damage and promote recovery.

In research published in the Proceedings of the National Academy of Sciences (PNAS), the researchers say their findings may hold promise for the treatment of human traumatic brain injury, a condition they say affects almost half a million Americans a year and which is currently untreatable.

“Our research suggests that it might be possible to effectively prevent much of the injury-induced brain damage,” said the study’s principal investigator, Alan Faden, MD, Professor of Neuroscience, Neurology and Pharmacology at Georgetown University Medical Center, and Director of the Laboratory for the Study of Central Nervous System Injury.

“We always have to be cautious in predicting human outcome from a study in rats, but the prevention of brain damage that we saw in this study is nothing short of remarkable,” he said. Rats untreated after head injury were left 28 days later with a large hole in their brain from death of cells surrounded by a scar, whereas the brains in those rats treated with the experimental drug, Flavopiridol, were nearly intact, with cognitive and motor function recovered, Faden said. “These rats were no different from the ones that had not experienced brain injury,” he said.

The approach that Faden and his research team have taken was suggested by findings from extensive gene studies conducted at Georgetown. Rather than trying to stop the earliest damage that results from the direct mechanical injury - the approach that is now most often used clinically - the Georgetown researchers took the tactic of trying to limit a second, and much larger, “wave of damage” which they have found usually peaks from 24-72 hours after injury. During this time, “glial” cells, which provide support and nutrition to neurons (the nerve cells that pass information throughout the brain) are pushed to divide extensively, producing scar tissue, Faden said.

Earlier work by the researchers had pinpointed genes that were turned on or off after trauma to the brain or spinal cord, and many of these were found to be involved in activating the “cell cycle,” which is required for glial cells to grow and divide. This proliferation produces a “glial scar” that can limit recovery. The same process also activates a type of glial cell, called microglia, that are involved in brain inflammation after injury.

At the same time, the cell cycle in neurons is activated, but because these nerve cells can no longer divide, they die. Combined with inflammation, this wave of damage then continues to progressively kill vital brain cells, the researchers have found.

“We reasoned that if you can shut down this delayed response to injury, then the lesion won’t spread, the scar won’t form, and you could save a lot of tissue that would have died,” said Simone Di Giovanni, MD, PhD, an Instructor in Department Neuroscience and first author on the paper.

To stop this damage, the researchers chose to test three drugs (flavopiridol, roscovitine and olomucine) that have been specifically designed to halt activation of the cell cycle. All three worked to stop progressive damage when tested in laboratory cell cultures. They then examined the use of flavopiridol in an experimental rat model of traumatic brain injury.

Flavopiridol, an anticancer drug, has already been tested in humans, but has not been proven successful because of the toxicity associated with sustained use, said Di Giovanni. But the researchers thought that it might work, and with limited side effects, if the drug was used just once.

So, in this study, they delivered flavopiridol to the animals 30 minutes after brain injury and found that it reduced expression of proteins that activated the cell cycle, thus limiting growth of the glial scar and formation of an inflammatory response. The size of the lesion was reduced by more than 80 percent, compared to rats who were not given the drug, and that resulted in a “remarkable improvement in tissue preservation and behavioral outcome,” said Di Giovanni.

Further work now shows that a beneficial response can be achieved in the rats even if the drug is delivered 24 hours after brain injury.

“This supports the concept that we now need to target the cell cycle in brain injury, whether it is with this drug or others,” Faden said.

Eventually, the researchers hope to use a drug of this type right after trauma, perhaps through an injection via the nasal passages - an idea Di Giovanni says the group is exploring.

The study was funded by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. Co-authors include, from Georgetown University: Vilen Movsesyan PhD, Farid Ahmed PhD, Ibolja Cernak MD, and Bogdan Stoica PhD, and Sergio Schinelli PhD, from the University of Pavia in Italy.

http://gumc.georgetown.edu