Laboratory studies at Johns Hopkins have revealed that
certain products of the enzymes COX-1 and COX-2 can both
protect and damage the brain. The findings, published in
the February issue of the Journal of Neurochemistry,
offer tantalizing clues to why drugs like Vioxx and
Celebrex, which block COX-2, can ease arthritis but
potentially harm the heart and brain.
Katrin Andreasson, an assistant professor in the
Neuroscience departments and lead author of the study,
explains that the recent discoveries of cardiovascular
complications with long-term use of some COX-2 inhibitors
are thought to be due to blocking effects of "good"
prostaglandins, which are the downstream products of COX
activity, potentially leading to heart attacks and strokes.
"Defining which prostaglandin pathways are good and which
promote disease would help to design more specific
therapeutics," she says.
In their latest laboratory studies, the Hopkins
scientists discovered that the prostaglandin PGD2 has a
protective or harmful effect in the brain depending on
where it docks on a brain cell's surface. After brain cells
experience the laboratory equivalent of a stroke, PGD2 can
protect them from being killed if it binds to one docking
point, or receptor, on the cells' surface but causes them
to die in greater numbers if it binds to a second receptor
instead, the researchers report.
Prostaglandins are involved in a wide variety of
bodily activities including relaxation and contraction of
muscles and blood vessels, control of blood pressure and
"PGD2 is the most-produced prostaglandin in the
brain," Andreasson says. "It trumps all of the rest. So we
theorized that high levels are protective. But it was a
surprise that it was so effective at protecting
Because the Johns Hopkins team found that PGD2's
positive effects generally outweigh its negative ones, the
group speculates that PGD2 may provide a potential target
for medicines to combat conditions involving brain damage,
including stroke, Parkinson's disease and Alzheimer's
In these neurologic diseases, nerve cell death is
thought to be carried out in part by a huge release of
glutamate, an important signaling molecule in the brain. In
their experiments with brain cells and brain tissue from
rats, the Johns Hopkins researchers used glutamate to
simulate the aftereffects of a stroke. After strokes and
other injuries to the brain, levels of glutamate rise,
triggering a number of chemical reactions, in-cluding an
increase in COX-2 production and prostaglandin production.
Increased COX-2 activity then leads to further neuron
The new findings come in the wake of two previous
studies Andreasson has worked on, each finding unexpected
protective roles for another prostaglandin produced by
COX-2. In one, a different prostaglandin, PGE2, prevented
brain cells from dying after a stroke. In the other, mice
lacking a docking point for the PGE2 experienced strokes
far more severe than those of normal animals.
Andreasson is now trying to determine if these
prostaglandins have a similar protective effect in mouse
models of Lou Gehrig's disease, in which excessive
glutamate is believed to damage neurons, and will begin
work to see if the beneficial side of PGD2 activity can
outweigh its toxic activity.
The studies were funded by the National Institute of
Neurological Disorders and Stroke and the American
Federation for Aging Research. Other authors of the study
were Xibin Liang, Liejun Wu and Tracey Hand, all from the
School of Medicine.