New Insights On Sequence of Cell Death After Brain Injury: Understanding Cellular Events After Brain Trauma Could Lead To Better Therapies

August 01, 1998

Brain injury due to motor vehicle accidents, falls, and sports accidents, among other reasons, affects nearly two million people every year, with related deaths claiming more than 56,000, according to the Brain Injury Association. Despite this, how the brain responds to injury -- in terms of the cellular cascade that leads to cell death -- is poorly understood. Looking at a particular pattern of cell death called apoptosis, or programmed cell death, researchers at the University of Pennsylvania Medical Center have discovered that in a rat model this kind of deleterious cellular destruction continues for weeks after the initial trauma.

"We hope that by understanding the molecular and cellular sequences of events after trauma, we'll be able to ascertain when and where cells die in the brain and use that information to develop new therapeutic strategies to treat injury," says Tracy K. McIntosh, PhD, professor of neurosurgery, bioengineering, and pharmacology. These insights could also apply to treating stroke, spinal cord injury, and perhaps neurodegenerative diseases. McIntosh and colleagues report their findings in the August 1 issue of the Journal of Neuroscience.

Classically, research in this field has focused almost exclusively on the first few days after an injury. Scientists hypothesized that this is when the maelstrom of neurochemical changes occurred, and after that, the brain's response calms down. "But this study points to the fact that things are not so quiet," comments McIntosh, who is also Director of Penn's Head Injury Center. "A brain-injured patient may look stable, but cells are still dying. Realizing this will be important for coming up with ways to recover, regenerate, and stem the loss of brain tissue. These findings could eventually effect protocols in rehabilitation and lead to ways to pharmacologically block cell death."

Alana C. Conti, a doctoral student in McIntosh's lab, charted the regional and temporal patterns of programmed cell death in the injured rat brains, at post-injury intervals of 12 hours to two months. The protracted time frame is unique to this study. Not all regions of the brain responded similarly. Early on, much of the programmed cell death occurred near the surface of the brain where the injury occurred. Then a progressive wave of cell death extended deeper into the brain, ending up in the thalamus, the region responsible for coordinating motor function.

In addition to the clear implications for treating brain injuries, this study adds to the growing basic knowledge of programmed cell death, an area of active research on many fronts. Apoptosis involves the expression of cell-death genes inside a particular cell. For example, apoptotic genetic programs cause some types of cancer cells to die.

"But in the brain, programmed cell death technically only occurs in developing brain cells in utero," explains McIntosh. "Cell death genes are expressed during development because there's an enormous amount of cellular redundancy in the fetal brain. The programmed cell death genes encode proteins that kill superfluous cells. Those genes get downregulated after birth and are not expressed, to our knowledge, in normal adults. Hence, one of the interesting things about this paper is that it documents that these genes are reactivated after a traumatic injury. Unfortunately, this is a destructive pathway that kills useful adult cells."

Penn colleagues John Q. Trojanowski, MD, PhD, professor of pathology and laboratory medicine, and Ramesh Raghupathi, PhD, research assistant professor in neurosurgery, also collaborated on the study. This research was supported by grants from the National Institutes of Health and the Veterans Administration.

Editor's Note: Dr. McIntosh can be reached at 215-573-3156 or mcintosh@eniac.seas.upenn.edu

The University of Pennsylvania Medical Center's sponsored research ranks third in the United States, based on grant support from the National Institutes of Health, the primary funder of biomedical research in the nation. In federal fiscal year 1997, the medical center received $175 million. News releases from the medical center are available to reporters by direct E-mail, fax, or U.S. mail, upon request. They are also posted to the center's website (http://www.med.upenn.edu) and EurekAlert! (http://www.eurekalert.org), a resource sponsored by the American Association for the Advancement of Science.
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University of Pennsylvania School of Medicine

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