"A lot of the previous findings kept bringing us back to PGE2 and its receptors," Doré said. "So we investigated whether it's possible to block the EP1 receptor so PGE2 couldn't trigger toxic effects."
Doré's team first injected either the EP1 blocker ONO-8713 or the EP1 stimulator, ONO-DI-004 into the ventricles (fluid-filled areas of the brain) of mice. A group of control mice received an injection of the solvent used to carry the drugs. The investigators then injected each mouse with NMDA, a drug that stimulates the NMDA receptor. Excessive stimulation of these receptors by NMDA, such as during stroke, leads to nerve cell damage.
In mice that had first received the EP1 stimulator ONO-DI-004, the area of brain damage was more than 28 percent greater than in control animals. The volume of damage in mice treated first with the EP1 blocker ONO-8713 was only about 71 percent that of controls.
"ONO-8713 significantly reduced brain damage in our mouse models following activation of a nervous-system response known to cause brain damage in humans during stroke," Doré noted.
The team next showed that in mice lacking the gene for the EP1 receptor, the volume of brain damage caused by stimulation of the NMDA receptor was only about 75 percent that of mice with the EP1 gene. This suggested that a significant part of the damage caused by activation of the NMDA receptor depends on the EP1 receptor. In addition, when the researchers injected the EP1 blocking drug ONO-8713 in mice lacking the gene for the EP1 receptor, the drug did not provide any additional protection. This suggested that ONO-8713 can exert its effect only by binding to the EP1 receptor, said Doré. "These findings demonstrate the critical role played by the EP1 receptor in brain damage caused by stroke," he added. "And they show that ONO-8
Source:Johns Hopkins Medical Institutions