July 23, 1999 Until recently, researchers in the area of head trauma have only concentrated on the biochemical sequence of events in the first few days after an injury. During the past year, however, investigators at the University of Pennsylvania Medical Center have found that the brain undergoes enormous changes for months following the initial damage. In the latest development in this ongoing work, the team found that tumor necrosis factor (TNF) -- a cytokine molecule that is normally released during inflammation -- may be damaging and then protective to brain-injured tissue, depending on the time course after the injury. The researchers report their findings in this week's issue of the Proceedings of the National Academy of Sciences.
The study has clear ramifications for treating brain trauma. "In the very early stages after head injury TNF may be harmful, so we'll probably want to block it with drugs, if possible," says Tracy K. McIntosh, PhD, professor of neurosurgery, bioengineering, and pharmacology and director of the Head Injury Center at Penn. "But if you continue to block or antagonize its effects, you may be doing some damage because it appears that in the chronic stages, TNF is important for recovery."
Using genetically engineered mice deficient in TNF, the team found that 48 hours after injury the TNF-knockout mice were less neurologically impaired than injured normal mice in tests of strength, balance, and coordination. The same held true for mice who underwent tests for memory retention seven days post-injury. But, by two to three weeks after the injury the normal mice recovered; whereas, TNF-knockout mice continued to show persistent motor deficits until at least four weeks, the length of the study. Over the long term, the TNF knockouts also had more cortical tissue loss than the normal mice.
"These findings bear out our hypothesis that in the acute period TNF is harmful to the brain, but in chronic stages TNF may play an important and beneficial role," notes McIntosh. Neuroscientists have long thought that inflammatory cytokines like TNFs are deleterious to the brain in terms of promoting neurodegeneration, much like that seen in stroke, Alzheimer's, and Parkinson's disease patients. On the other hand, in recent studies TNFs have also been implicated in such regenerative processes as wound-healing, nerve repair, and antioxidant pathways.
Although this study was aimed at probing the role of TNF in brain injury, it does hold potential lessons for treatment. "A drug company could conceivably develop a pharmacological strategy to block TNF, which could be given to head injury patients during the acute injury phase," says McIntosh. But the study also cautions that if a TNF blockade is continued into the chronic, post-traumatic phase, it could be harmful. The drug therapy would have to be discontinued so that TNF naturally present in the brain could promote long-term regeneration.
In addition to TNF, the McIntosh lab is studying another inflammatory cytokine. In a report to be published later this, the group analyzed the therapeutic value of an interleukin-1 receptor antagonist. By simply blocking interleukin-1 pharmacologically, memory loss and cell death were minimized in brain-injured rats.
Penn coauthors are Uwe Scherbel, Ramesh Raghupathi, Michio Nakamura, Kathryn Saatman, and John Trojanowski. These studies were funded in part by grants from the National Institutes of Health and the Veteran's Administration.
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