Blocking the nerve receptor EP1 in mouse models reduces brain damage caused by stroke

December 20, 2005

Researchers at Johns Hopkins have discovered how to block a molecular switch that triggers brain damage caused by the lack of oxygen during a stroke. The Hopkins study, conducted on mice, is believed to be the first to demonstrate that a protein on the surface of nerve cells called the EP1 receptor is the switch, and that a specific compound, known as ONO-8713, turns it off.

The finding holds promise for the development of effective alternatives to anti-inflammatory drugs called COX inhibitors, which have potentially lethal side effects that limit their use, says Sylvain Doré, Ph.D., an associate professor in the departments of Anesthesiology and Critical Care Medicine and Neuroscience at The Johns Hopkins University School of Medicine. Doré is senior author of the paper, published in the January issue of Toxicological Sciences. "Our work has shifted the focus from drugs that inhibit COX-2 to drugs that block the EP1 receptor," Doré said.

Receptors are protein-docking sites on cells into which "signaling" molecules such as nerve chemicals or hormones insert themselves. This binding activates the receptor, which transfers the signal into the cell to produce a specific response.

COX inhibitors block the ability of the enzyme cyclooxygenase-2 (COX-2) to make prostaglandin E2 (PGE2), a hormonelike substance long linked to inflammation and other effects. The Hopkins study results suggest that PGE2 causes brain damage following stroke by binding to the EP1 receptor on nerve cells. Therefore, blocking PGE2 activity directly rather than inhibiting COX-2 could reduce brain damage in individuals who have a stroke while avoiding the side effects of COX-2 inhibitors, the Hopkins investigators say.

Previous work by others had shown that certain events, such as cerebral ischemia (stroke) and seizures, that interrupt oxygen flow to the brain also cause excessive activation of so-called NMDA receptors by the nerve chemical glutamate. Other work had suggested that activation of NMDA receptors by glutamate causes an increase in the production of COX-2, which then produces PGE2.

"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-8713 works specifically at that receptor."

Finally, the Hopkins scientists showed that stimulation of EP1 receptors triggers the damage caused when blood flow is suddenly restored after a stroke. The team blocked blood flow in one of the main arteries feeding specific areas of the brain in mice lacking the gene for the EP1 receptor and then restored blood flow after 90 minutes. The area of brain damage (infarct size) in the mice lacking the EP1 gene was only about 57 percent of that seen in normal mice that underwent the same treatment. This provided additional evidence that brain damage caused by ischemia depends in large part on the stimulation of EP1 receptors, the researchers reported.

"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," said Doré.

Doré has applied for a patent covering the prevention and/or treatment of neurodegenerative diseases by administering agents that block the EP1 receptor.
-end-
Additional contributing authors of the paper include postdoctoral fellow Abdullah Shafique Ahmad, Ph.D.; postdoctoral fellow Sofiyan Saleem, Ph.D.; and research fellow Muzamil Ahmad, Ph.D., all of the Department of Anesthesiology and Critical Care Medicine at Hopkins.

This work was supported in part by the National Institutes of Health and a postdoctoral fellowship from the Mid-Atlantic American Heart and Stroke Association.

Johns Hopkins Medicine

Related Stroke Articles from Brightsurf:

Stroke alarm clock may streamline and accelerate time-sensitive acute stroke care
An interactive, digital alarm clock may speed emergency stroke care, starting at hospital arrival and through each step of the time-sensitive treatment process.

Stroke patients with COVID-19 have increased inflammation, stroke severity and death
Stroke patients who also have COVID-19 showed increased systemic inflammation, a more serious stroke severity and a much higher rate of death, compared to stroke patients who did not have COVID-19, according a retrospective, observational, cross-sectional study of 60 ischemic stroke patients admitted to UAB Hospital between late March and early May 2020.

'Time is vision' after a stroke
University of Rochester researchers studied stroke patients who experienced vision loss and found that the patients retained some visual abilities immediately after the stroke but these abilities diminished gradually and eventually disappeared permanently after approximately six months.

More stroke awareness, better eating habits may help reduce stroke risk for young adult African-Americans
Young African-Americans are experiencing higher rates of stroke because of health conditions such as high blood pressure, diabetes and obesity, yet their perception of their stroke risk is low.

How to help patients recover after a stroke
The existing approach to brain stimulation for rehabilitation after a stroke does not take into account the diversity of lesions and the individual characteristics of patients' brains.

Kids with headache after stroke might be at risk for another stroke
A new study has found a high incidence of headaches in pediatric stroke survivors and identified a possible association between post-stroke headache and stroke recurrence.

High stroke impact in low- and middle-income countries examined at 11th World Stroke Congress
Less wealthy countries struggle to meet greater need with far fewer resources.

Marijuana use might lead to higher risk of stroke, World Stroke Congress to be told
A five-year study of hospital statistics from the United States shows that the incidence of stroke has risen steadily among marijuana users even though the overall rate of stroke remained constant over the same period.

We need to talk about sexuality after stroke
Stroke survivors and their partners are not adequately supported to deal with changes to their relationships, self-identity, gender roles and intimacy following stroke, according to new research from the University of Sydney.

Standardized stroke protocol can ensure ELVO stroke patients are treated within 60 minutes
A new study shows that developing a standardized stroke protocol of having neurointerventional teams meet suspected emergent large vessel occlusion (ELVO) stroke patients upon their arrival at the hospital achieves a median door-to-recanalization time of less than 60 minutes.

Read More: Stroke News and Stroke Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.