New Group of Compounds Could Help Protect Brain Cells from Stroke or Seizure

Scientists at Emory University School of Medicine have identified a new group of compounds that may protect brain cells from toxicity after a stroke or seizure.

The results were published online Jan. 14 in the Proceedings of the National Academy of Sciences.

The compounds selectively enhance signals from one of the four receptors for prostaglandin E2. Prostaglandins are hormones involved in fundamental processes such as pain, inflammation, digestion and blood pressure regulation. Previous studies in animals suggest that prostaglandin E2 can have both helpful and harmful effects on the brain after a stroke or seizure, depending on which molecules carry out its effects.

“Because modulating prostaglandins can have complex results, our strategy here was to go downstream and focus on one set of receptors,” says senior author Ray Dingledine, PhD, chairman of Emory’s Department of Pharmacology.

Prostaglandins are the targets for non-steroid anti-inflammatory drugs such as aspirin and naproxen, which inhibit enzymes known as cyclooxygenases, the starting point for generating prostaglandins in the body.

A well-known side effect of taking aspirin is weakening the stomach lining, coming from prostaglandins’ role in the stomach. Even drugs designed to inhibit only cyclooxygenases involved in pain and inflammation have displayed harmful side effects: clinical studies showed that patients taking selective cyclooxygenase inhibitors experienced higher rates of heart attack and stroke compared to patients taking naproxen.

Working with Yuhong Du and Pahk Thepchatri in the Emory Chemical Biology Discovery Center, postdoctoral fellows Jianxiong Jiang and Thota Ganesh sorted through a library of 292,000 compounds to find those that could enhance signals from the EP2 prostaglandin receptor but not similar receptors.

Two of the compounds could protect neurons from stimulation that models the “excitotoxic” environment in the brain during a stroke or seizure.

Dingledine says that the compounds could become valuable tools for exploring new ways to treat neurological diseases. However, given the many physiological processes prostaglandins regulate, more tests are needed, he says. Prostaglandin E2 is itself a drug used to induce labor in pregnant women, and female mice engineered to lack the EP2 receptor are infertile, so the compounds would need to be tested for effects on reproductive organs, for example.

The research was supported by the National Institutes of Health.

Reference:
J. Jiang et al. Neuroprotection by selective allosteric potentiators of the EP2 prostaglandin receptor. PNAS online before print 2010. Doi: 10.1073/pnas.0909310107

Writer: Quinn Eastman

###

The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include the Emory University School of Medicine, Nell Hodgson Woodruff School of Nursing, and Rollins School of Public Health; Yerkes National Primate Research Center; Emory Winship Cancer Institute; and Emory Healthcare, the largest, most comprehensive health system in Georgia. Emory Healthcare includes: The Emory Clinic, Emory-Children’s Center, Emory University Hospital, Emory University Hospital Midtown, Wesley Woods Center, and Emory University Orthopaedics & Spine Hospital. The Woodruff Health Sciences Center has a $2.3 billion budget, 18,000 employees, 2,500 full-time and 1,500 affiliated faculty, 4,500 students and trainees, and a $5.7 billion economic impact on metro Atlanta.