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COX-2: The Little Molecule that Shouldn't
New studies show a chronic wash of the enzyme may
predispose to stroke.




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A quiet process starting in middle age may put out the welcome mat for
stroke. It's a change made even more potent by the usual baddies
associated with that event -- hypertension, diabetes, suspect arteries
-- and it involves a gradual climb in the enzyme cyclooxygenase-2.
 "COX-2 is widely distributed in the brain and normally assumes a useful
role," says neurologist Kati Andreasson, M.D., whose laboratory hours
are largely spent in clarifying the enzyme's activity. COX-2 appears
when synapses are active. It's a key player in the plasticity of brain
neurons, Andreasson and colleagues have found, sitting as it does on the
delicate dendritic spines where changes translate into learning and
memory.

"But in greater amounts, there's a different story," she says. She
likens COX-2 to the two-faced god, Janus. "The face you get," she
explains, "depends on the situation." COX-2 is an inducible enzyme,
called forth by the neurotransmitter glutamate. In acute situations, as
in stroke or seizures, when glutamate pours out of neurons, there's a
subsequent wash of COX-2. Studies show the sudden excess is toxic.
Recently, however, Andreasson's research suggests that a chronic swell
in the enzyme is also damaging, though in a subtler way.

In work reported in the Annals of Neurology, her team employed a mouse
model of stroke that temporarily blocks the middle cerebral artery. The
event destroys nearby deep brain tissue while cutting blood flow to-and
endangering-cortical areas. But Andreasson also used the stroke model to
follow animals engineered to overproduce COX-2: mice carrying
switched-on human COX-2 genes. Then, the size of their brain infarct
swelled 20 percent. "We expected that," Andreasson says, "knowing COX-2
as we do."

What she didn't expect, however, was the difference in the two mouse
types when the enzyme was inhibited. Standard mice receiving a COX-2
blocker before the stroke saw a dramatic reduction in volume of lost
brain tissue. "That wasn't the case with the transgenic mice, though,"
says Andreasson. "They seemed immune to inhibition's good effects. That
suggests chronic, low-level COX-2 activity somehow alters neurons,
making them more fragile or vulnerable to insult."

Combine this idea with the team's study showing the gradual enzyme rise
in aging brains and that might explain why strokes tend to be more
damaging in older people. "And there are other negatives here," she
adds. "Hypertension, diabetes, poor glucose metabolism are all stroke
risk factors. They all also increase COX-2." What about other disorders
that begin in older adults-Parkinson's disease, ALS or Alzheimer's? High
COX-2 could be an added insult, she says. Heightened levels mark those
diseases.

Now the team hopes to explain how the enzyme causes problems. They've
focused on COX-2's key offshoots, the prostaglandins. Those are the same
molecules that bedevil headache sufferers and arthritis patients, all
who swallow Celebrex or Advil for their prostaglandin- damping effects.

But in what Andreasson cautiously describes as "outright heresy," she's
found not all prostaglandins are bad. Some are apparently
neuroprotective, her work shows. She may have unearthed a natural system
of checks and balances within the nervous system, an idea that could
soon become the darling of pharmaceutical companies.

For more information, call 410-614-2014.
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