"This work may open up therapeutic avenues for people who need radiation treatment," said Michelle Monje, an MD/PhD student and first author on the paper. The work, led by Theo Palmer, PhD, assistant professor of neurosurgery, and co-authored by postdoctoral scholar Hiroki Today, MD, PhD, will be published in the Nov. 14 advance online issue of the journal Science and in the Dec. 5 print edition.
People with brain tumors and leukemia often receive radiation therapy to destroy cancerous cells. But that treatment also damages healthy brain cells - in particular those cells in the memory center of the brain, called the hippocampus. This damage leads to serious problems with memory and learning. Memory loss is especially noticeable in children who undergo whole-brain radiation, the majority of whom end up in special education classes after the procedure, according to Monje.
Doctors had hoped that implanting brain stem cells - cells that reside in the brain and can form into any brain cell type - could replace the lost neurons. But those relief worker cells rarely flourish in their transplanted home. "They are still there, but they can't do their job," Monje said. "Something was wrong in the environment where the stem cells should be making neurons."
Monje and Palmer suspected the culprit might be inflammatory cells that rush to the site of radiation or injury-induced damage. This idea arose in part because people with Alzheimer's disease or other forms of dementia associated with brain inflammation often fare better when they receive a group of drugs called nonsteroidal anti-inflammatory drugs, or NSAIDs, that foil inflammation.
Monje tested this idea both in a lab dish and in rats. First, she injected a substance into rats that is known to cause inflammation. Compared with rats that received a placebo injection, those that received the inflammatory substance had far fewer new neurons a week after the injection.
In a second round of experiments, she treated the injected rats with twice-daily doses of an NSAID. One week later, stem cells were making neurons as regularly as in rats without an inflammation-causing injection. Monje switched to a laboratory dish to learn how inflammation thwarts brain stem cell activity. She found that the stem cells exposed to either inflammatory cells or to the molecular by-products of inflammatory cells were less likely to make neurons.
She narrowed the list of offending molecular by-products to two candidates - called IL-6 and TNF-alpha - both of which are churned out by cells that cause inflammation. Monje repeated the experiment but added a substance that blocks the effects of IL-6. These stem cells were able to form normal neuronal cells.
In a final experiment to test the effectiveness of NSAIDs, Monje exposed rats to radiation then gave them regular doses of NSAIDs. Compared to rats that didn't get the anti-inflammatory drug, these treated rats had significantly more new neurons in their hippocampus.
According to Monje and Palmer, the next step is to learn whether giving people NSAIDs after radiation therapy or other brain injury could help prevent long-term brain damage. Palmer cautioned that although the early work is promising, further studies will need to show that the NSAIDs themselves don't interfere with other necessary medical treatments.
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