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Study of cox-2 inhibitors could lead to new class of stroke drugs by ferujkll sdff
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Study of cox-2 inhibitors could lead to new class of stroke drugs |
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A study, in mice, by investigators at the Stanford UniversitySchool of Medicine points toward potential new therapies for stroke , the nation's third-leading cause of death and foremost singlecause of severe neurological disability. The study, which will bepublished online Oct. 3 in the Journal of Clinical Investigation , also may reveal why a much-heralded class of blockbuster drugsfailed to live up to their promise. Medical experts were excited when over a decade ago a class ofdrugs called COX-2-selective inhibitors came along. These new drugswere supposed to retain the advantages of aspirin and otherso-called non-steroidal anti-inflammatory drugs , or NSAIDs, without causing stomach damage.
But in large-scale clinical trials of COX-2-selective inhibitors,puzzling - and disturbing - side effects emerged: namely, anincreased risk of heart attacks and strokes. One already-approved drug in this category, rofecoxib( Vioxx ), was pulled from the market in 2004. Another drug in this classis celecoxib, or Celebrex. The new study helps explain why these drugs can be troublesome andhow there may actually be some benefits to reap from the verymolecular activity that these drugs were intended to block.
"Someof what COX-2 does, it turns out, is good," said Katrin Andreasson,MD, associate professor of medicine and the study's senior author. NSAIDs block both COX-2 and COX-1, two very similar versions ofcyclo-oxygenase, an enzyme that catalyzes a key chemical reactionin the production of five related hormone-like messenger moleculescalled prostaglandins. The workings of COX-1 and COX-2 cause thesefive prostaglandin types to be produced in different ratios. Prostaglandins travel from one cell to another, landing on andbinding to dedicated receptor molecules sitting on cells' surfacesand stimulating various activities inside those cells. Each type ofprostaglandin can trigger distinct effects.
One prostaglandin inparticular, PGE2, is known to be associated with pain andinflammation. Because PGE2 is produced in relative abundance by COX-2 action,COX-2-selective inhibitors cause PGE2 levels to drop bothabsolutely and relative to the other prostaglandins. That makesthem effective pain relievers. But Andreasson wanted to understandwhy they can cause strokes.
PGE2 has four separate counterpart receptors, designated EP1through EP4, each of which sets in motion a different set ofactivities inside cells on binding to PGE2. Andreasson's team useda mouse model of stroke to show that activating one of thesereceptors, EP4, after a traumatic brain event such as a stroke canbe very beneficial. In the early 2000s, Andreasson carried out studies indicating thatCOX-2 activity is normally quite strong in nerve cells, where itappears to be involved in physiological changes underpinninglearning. Now, in the new study, she and her colleagues found thatamounts of EP4 on both nerve cells and the endothelial cells thatline the blood vessels of the brain increase substantially after astroke.
"This, to us, suggested that the EP4 receptor may be doingsomething important," she said. Andreasson's team employed a compound that selectively binds to andactivates EP4 to show that administering this compound by injectionas much as three hours after a stroke reduced the amount of braindamage the mice suffered. Importantly, a single injection of thiscompound three hours after a stroke enhanced mice's behavioralrecovery from the stroke, as measured a full week later by theirsuperior performance on a test of motor coordination. The researchers then examined the independent effects of EP4activation on nerve cells and endothelial cells.
Adding thecompound increased the survival of nerve cells in a dish after thecells had been stressed by conditions similar to a stroke. Inendothelial cells, EP4 activation by the compound resulted in anincreased production of nitric oxide, a key chemical that amongother things diffuses to nearby smooth muscle cells surroundingblood vessels, relaxing them. This lets the blood vessels dilate,enhancing blood flow. Inactivation, via a sophisticated genetic manipulation, of the EP4receptor on the mice's nerve cells both increased stroke severityin the mice and worsened their recovery. Similarly inactivating thereceptor on endothelial cells worsened stroke injury and decreasedblood flow to the affected area.
The only currently approved drug for stroke is tissue plasminogenactivator, or tPA, which dissolves clots that prevent oxygenatedblood from reaching brain tissue. But tPA does nothing to counterthe damage caused after the stroke by inflammatory agents thatflood into the affected tissue. New treatments for thisdebilitating disorder are desperately needed, Andreasson said. Adrug that increased blood flow from still-functioning vasculatureto the stroke region, as the EP4-activating compound does, mightcomplement tPA's effect, she added.
"We showed that activating this single receptor, EP4, three hoursafter a stroke not only diminishes the volume of a mouse's affectedbrain tissue but also enhances the mouse's functional recovery,"said Andreasson. "And we've taken this a step further by diligentlyunraveling the mechanisms by which that happens." Andreasson's laboratory is now exploring the behavioral recovery ofmice given the EP4-activating compound after longer post-strokewaiting times. She said she wants to see whether the therapeuticwindow can be extended to more than six hours after a stroke, whichcould greatly increase the value of such a treatment. Andreasson cautioned that many therapies, even when highlysuccessful in mice, fail in the clinic. I am Luggage Cart writer, reports some information about oil room heaters , delonghi oil heaters.
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