Bringing Failing Brain Cells Back

With RWJF support, Harold Amos Scholar researches a promising approach to treating traumatic brain injury in children and adolescents.

    • February 28, 2012

Traumatic brain injury (TBI) is a leading cause of death and disability in children and adolescents. It also is uniquely challenging to manage in young patients, who can’t tolerate some of the more aggressive diagnostic and treatment approaches used on older patients. With a four-year Robert Wood Johnson Foundation (RWJF) grant, Jose Pineda, MD, MSc, has developed more child-friendly ways to assess how TBI unfolds at the cellular level—the first step in treating injury at that level to promote recovery.

Pineda is a scholar (2009-2013) in RWJF’s Harold Amos Medical Faculty Development Program, an assistant professor of pediatrics and neurology at Washington University School of Medicine in St. Louis, Mo., and director of the Neurocritical Care Program at St. Louis Children’s Hospital.

Understanding how young patients’ brain cell metabolism is disrupted after TBI will be key to developing new treatment therapies, Pineda says. He and four co-authors describe one approach to gauging that metabolic dysfunction in the February 2012 edition of the journal, Pediatric Research.

The research conducted by Pineda and colleagues centers on mitochondria, the structures in brain cells that provide energy and govern processes such as cell death. Pineda likens the mitochondria’s function to that of “a nuclear power plant. In terms of energy production, it’s very efficient. But if it fails, you have two problems. Number one, you have no energy. And number two, there are harmful messengers leaking out of the failed mitochondria. Those messengers initiate the process of cell damage—they basically tell enzymes to start chewing up proteins,” resulting in cell death.

Studies in animals and adult humans have shown that the cascading failure effect can continue for days after a TBI, causing more damage beyond the initial injury and hampering recovery, Pineda says. Studies in animals, chiefly rodents, also have shown that some pharmacologic therapies can protect the mitochondria from failure, restoring energy production and preventing the release of chemicals that trigger cell death.

“But just because we see that happening in a lab rat doesn’t mean it’s happening in a human,” says Pineda. “And studies that could be attempted with adult humans could not be tried, and might not work the same, in younger patients. For example, scientists have examined mitochondria from test rats’ brains and from adult human brain tissue that was surgically removed as part of treatment. But as a pediatric brain specialist,” Pineda says, “I cannot do that, as children hardly ever go to the operating room, much less to have small pieces of the brain removed. So we have to be able to find ways to measure or to support the case that there is mitochondrial failure after TBI in children without touching the brain.”

To do that, Pineda and colleagues used magnetic resonance (MR) imaging to look at possible indicators of mitochondrial failure. With a recently-developed scanning technique, they looked at how children’s brain cells were extracting oxygen from the blood circulating in the brain. The scans showed that in children with TBIs, the amount of oxygen the brain extracted was depressed—suggesting the mitochondria were failing to metabolize it—and that the extracted oxygen levels were lowest where TBI was most severe. Pineda and colleagues knew the decreased oxygen uptake could indicate that brain cells had died—or only that mitochondria were failing and that, if they could recover, further cell death might be prevented.

Pineda’s team sought another marker to test that possibility. In a study presented at the Pediatric Academic Societies annual meeting in 2011, they scanned young TBI patients’ brains for the presence of N-Acetylaspartate (NAA). A molecule produced in the mitochondria of neurons, NAA gives off one of the strongest signals in brain MR images. NAA historically was seen in lower concentrations in children with TBI, Pineda says. “But what would happen if we measured it shortly after injury, and then again three months later? If the neurons are dead and gone, it would stay flat. But if this is just a transient failure of the mitochondria, then the NAA will go up. And that is what we showed, for the first time: that after TBI, the mitochondria is failing but attempts to recover. That, to me, means an opportunity for treatment.”

By using non-invasive, child-safe measures to study oxygen extraction and NAA concentration in the brain, “we are supporting previous work in animal models that indicates mitochondrial failure after TBI – and that will help make the case for creating drug therapies to use as soon as possible after TBI to protect the mitochondria,” says Pineda. “These studies are very complex, expensive, and hard to do and can take years. It has been a long journey, and I have done it this way because I believe you only get a few shots in your career to try to make a difference, and when testing a therapy I want to go into a clinical trial with the best possible chance of success. The Robert Wood Johnson Foundation understood this, and supported me for four years to stay on the case.”

Pineda says three or four drugs that have been tested in animals and in adult brain tissue have shown promise in stemming mitochondrial dysfunction. Given his team’s findings about how that dysfunction affects children after TBI, clinical trials of the drugs for child and adolescent patients “could be a year or two away,” he says.

The study, “Depression of Whole-Brain Oxygen Extraction Fraction is Associated with Poor Outcome in Pediatric Traumatic Brain Injury,” is published in the February 2012 edition of the journal, Pediatric Research. The co-authors with Pineda are Dustin K. Ragan,PhD; Robert McKinstry, MD, PhD; Tammie Benzinger, MD, PhD; and Jeffrey Leonard, MD. An abstract of the presentation,
N-Acetylaspartate and Recovery in Children with Traumatic Brain Injury, can be viewed online.

The Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program (AMFDP) was created to make it possible for scientists, physicians and dentists from historically disadvantaged backgrounds to advance to senior positions in academic medicine. The four-year, AMFDP supports biomedical, clinical, dental, and health services/epidemiology research. Awards are offered to physicians and dentists who are not only committed to building careers in academic medicine and dentistry, but who hope to serve as role models for other students and faculty members from disadvantaged backgrounds.

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