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Anti-Inflammatory Drugs Restore Neuron Growth in the Brain
  
By Edward R. Winstead

Image at left shows abundance of newborn neurons in rat brain; the neurons are significantly reduced by inflammation (right).
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Most children who have radiation therapy to eradicate a brain tumor come through the treatment free of cancer but go on to develop learning and memory problems not unlike those seen in Alzheimer's patients. The decline begins many months or years after the treatment and is currently irreversible. Now scientists are starting to understand why.

“It's very sad because these children survive the cancer but later on develop cognitive problems and often end up in special education or institutionalized,” says Theo D. Palmer of the Department of Neurosurgery at Stanford University.

In an effort to understand why radiation to the brain causes cognitive decline, Palmer and two colleagues conducted experiments in rats and learned that inflammation caused by radiation blocks the production of new neurons in the hippocampus, which usually generates thousands of neurons every day. This region is critical for learning and creating new memories.

“We found that rats exposed to radiation stopped producing neurons, and part of the reason they stopped was inflammation,” says Palmer.

Swedish researchers working independently made the same discovery at virtually the same time.

“Both studies found that new neurons are very sensitive to inflammation,” says Olle Lindvall, of Lund University Hospital in Sweden , who expressed surprise at how detrimental inflammation is to the production of new neurons.

There is some good news. Both teams found that anti-inflammatory drugs restored the growth of new neurons in injured rats.

The Stanford team used indomethacin, an anti-inflammatory usually prescribed to relieve the pain and swelling caused by arthritis, gout and other conditions. The drug might be used to help restore neuron growth in the human brain.

Before that happens, however, researchers need to know how to block only harmful inflammation. Some inflammation, which occurs when cells respond to an injury such as radiation or a stroke, is important in destroying brain tumors.

Palmer is cautiously optimistic that further research may show that an anti-inflammatory drug given at the right time during radiation therapy could benefit patients and improve their quality of life after therapy. Diminishing or preventing the damage could be as simple as taking a pill twice a day at specific times during the treatment, he says.

The research is published today online in the journal Science. Another member of the Stanford study, Michelle L. Monje, recently presented the findings at the 2003 Society for Neuroscience meeting in New Orleans.

“There is a great deal of interest from both parents and the doctors who treat childhood cancer patients to find a solution to this devastating problem,” Monje says.

Indomethacin is a prescription drug closely related to ibuprofen, which, like aspirin, is a non-steroidal anti-inflammatory drug (NSAID). Collaborators of the Stanford team are testing a variety of NSAIDs to see which one might work best in a clinical setting.

The Swedish study, which appeared online in Proceedings of the National Academy of Sciences a few weeks ago, involved minocyline, an antibiotic that has anti-inflammatory properties.

The studies together, says Lindvall, suggest a link between inflammation and the suppression of new neurons that may contribute to cognitive decline in people with brain diseases. The challenge now is to determine the degree to which the loss of new neurons in the brain contributes to cognitive problems.

The researchers hope in the coming years to find ways to improve the brain's response to injury. This will almost certainly require learning more about stem cells—the cells that generate new neurons—and how they behave in the presence of inflammation.

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Ekdahl, C.T. et al. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci USA 100, 13632-13637 (November 11, 2003).

 

Monje, M.L. et al. Inflammatory Blockade Restores Adult Hippocampal Neurogenesis. Published online in Science (November 13, 2003).

 

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