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Pain Molecule Linked to Brain Changes

Cox-2 enzyme promotes memory loss in mice

MONDAY, Nov. 19, 2001 (HealthDayNews) -- Mice with an overabundance in the brain of an important pain molecule appear to be at increased risk of age-related mental decline, a new study says.

The findings, presented last week at a neuroscience meeting in San Diego, haven't yet been linked to people. But researchers say the work hints that drugs that inhibit the molecule -- medications already immensely popular for the treatment of arthritis -- might prevent memory loss related to strokes, Alzheimer's and Parkinson's diseases, and related disorders.

Scientists, in fact, are now looking at whether inhibiting the molecule, cyclooxygenase-2 (cox-2), can prevent Alzheimer's disease in older Americans at elevated risk of the malady. The decade-long trial, which includes almost 3,000 people over age 70, is comparing a placebo with a cox-2 inhibitor called Celebrex and a non-steroidal anti-inflammatory drug (NSAID) called naproxen, which blocks cox-2's sister molecule, cox-1.

Dr. Pierre Tariot, a University of Rochester psychiatrist leading one arm of that trial, says almost two dozen studies have shown that people who regularly take NSAIDs for pain and other symptoms can markedly reduce their risk of dementia. But because cox-2 blockers are so new to the market, having won approval in the last few years, it's not clear whether they'll have the same effect.

"The optimist's hypothesis is that these therapies, singly or both, will reduce the conversions to Alzheimer's disease," says Tariot, referring to both cox-1 and cox-2 inhibitors.

Cox-2 is an inflammatory molecule found throughout the body and in the brain. Cox-2 inhibitors, including Celebrex and Vioxx, have become blockbuster drugs for arthritis, and Celebrex has also won government approval to treat certain forms of colon tumors.

Animal studies have shown that brain injuries like strokes trigger a rush of cox-2 in several regions, in response to a surge in another compound called glutamate. Under normal circumstances, brain cells produce just enough glutamate to guarantee a healthy flow of calcium, an important signaling molecule. But after a stroke or other trauma, neurons overproduce glutamate, releasing a flood of calcium that ultimately leads to their death.

In the new work, which appeared in a recent issue of the Journal of Neuroscience, Dr. Katrin Andreasson, a Johns Hopkins University neurologist, and her colleagues created a clan of genetically engineered mice that produce abnormally high amounts of cox-2 in their brain.

At seven months of age -- which would be roughly equivalent to someone between 20 and 30 years old -- the animals had no trouble on standard tests of mental ability, including maze running and swimming exercises. But at 12 and 20 months, they showed significant cognitive declines, and at the latter age they also displayed behavioral changes.

Brain tissue samples showed that, compared with genetically normal rodents, the engineered mice had more severe age-related loss of brain cells.

Dr. John Smythies, a cox-2 expert at the University of California at San Diego, says too much cox-2 sets off a chain reaction involving molecules called prostaglandins. They eventually cause a glut of toxic oxygen derivatives, which in turn destroy a delicate balance in the synapses where brain cells trade signals.

"Inhibiting this enzyme might have two effects, depending on the balance of oxygen [derivatives]," Smythies says. "If you do it very strongly, you could cut off the supply of reactive oxygen species" to the synapses. Although that might help improve neuron function, too sharp a correction could hinder it, he says, because some reactive oxygen activity is important for healthy messaging in the brain.

What To Do

For more on cox-2 blockers, try Johns Hopkins University.

To learn more about arthritis, try the Arthritis Foundation.

Celebrex has also been approved for the treatment of a rare form of hereditary colon tumor.

For more on Alzheimer's disease, try the Alzheimer's Association.

SOURCES: Interviews with Pierre Tariot, M.D., professor of psychiatry, University of Rochester, Rochester, N.Y.; John Smythies, M.D., director, division of neurochemistry, center for brain and cognition, University of California, San Diego; Oct. 15, 2001, Journal of Neuroscience
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