Stroke Damage Modulated by EP1 Receptors

A control group received only the solvent used to carry the drugs. All the mice were then injected with NMDA (N-methyl-D-aspartic acid) to trigger a simulated stroke.

NMDA mimics the action of the neurotransmitter glutamate on NMDA receptors. These receptors play a critical role in synaptic plasticity mechanisms, and thus are necessary for several types of learning and memory. Activation of NMDA receptors causes an increase in the production of the COX-2 enzyme, which produces the prostaglandin PGE2. PGE2 has been linked to inflammation and other deleterious effects and is suspected of causing brain damage following stroke by binding to the EP1 receptor on nerve cells.

Results published in the January 2006 issue of Toxicological Sciences revealed that the mice that had first received the EP1 stimulator ONO-DI-004 suffered 28% more brain damage than did the control animals, while those animals treated with the EP1 blocker ONO-8713 suffered 29% less damage than did the controls.

The experiment was repeated with a line of mice genetically engineered to lack the gene for EP1. Following NMDA treatment it was found that the control group experienced 25% less damage than had the wild type controls. ONO-DI-004 did not increase the extent of the damage, and ONO-8713 did not reduce it.

These results suggested that ONO-8713 could exert its effect only by binding to the EP1 receptor. Senior author Dr. Sylvain Doré, associate professor of anesthesiology and neurosciences at John Hopkins University, explained, "These findings demonstrate the critical role played by the EP1 receptor in brain damage caused by stroke, and they show that ONO-8713 works specifically at that receptor. Our results strongly suggest that given the side effects associated with COX inhibitors, we should focus our efforts on developing drugs that block the EP1 receptor instead of inhibiting COX-2 activity.”



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