Antioxidant tempol prevents pre-eclampsia, decreases fetal mortality in mice

The antioxidant tempol prevents the onset of pre-eclampsia in pregnant mice, a finding that further implicates oxidative stress in the illness, which is widespread among pregnant women.

According to lead researcher Darren S. Hoffmann, tempol

  • cut fetal deaths in half
  • normalized birth weight and placental development
  • prevented the onset of high blood pressure and proteinuria

"The results strongly suggest that antioxidant therapy will be useful for women with pre-eclampsia," Hoffmann said. Hoffmann received a Caroline tum Suden/ Frances A. Hellebrandt Professional Opportunity Award from The American Physiological Society (APS) for the exemplary research. The paper will be presented in an APS session at Experimental Biology 2006.

*Paper presentation: "Superoxide scavenging improves early placental development and fetal growth and survival in a mouse model of pre-eclampsia," 12:45 p.m. - 3 p.m., Sunday April 2, Physiology Genetic Models of Cardiovascular Function, 212.8/board #C386. On view 7:30 a.m. - 6 p.m. Research was by Darren S. Hoffmann, Christine J. Weydert, Ram V. Sharma and Robin L. Davisson, Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA.

Cause of pre-eclampsia unclear

Pre-eclampsia has been recognized as a threat to maternal health for centuries and is the leading cause worldwide of mortality during pregnancy. But its cause has remained a mystery, Hoffmann said. The condition is marked by high blood pressure and kidney dysfunction, and occurs in about 5% of pregnancies. The only way to reverse the condition, which occurs in the third trimester, is to induce early delivery, he said.

The condition is often treated by complete bed rest. But managing the condition is a delicate balance pitting the needs of the mother, who is suffering a potentially harmful condition, against the needs of the fetus, which is best served by remaining in the womb.

Pre-eclampsia occurs when the placenta fails to develop properly and the fetus is unable to get adequate nutrients from the mother, Hoffmann explained. That sets off a cascade of events that can result in damage not only to the fetus, but also to the mother's kidney and blood vessels. If left unchecked, the condition could lead to eclampsia, an even more serious illness marked by seizures.

In areas where women do not have access to medical care, the condition causes death in one in 650 pregnant women, Hoffmann said. Even in the U.S., pre-eclampsia is the leading cause of maternal mortality. And even when the condition is well managed, it often results in having to induce a premature birth, which carries substantial economic cost. On average, neonatal care for premature infants costs $40,000, he said.

Oxidative stress a suspect in pre-eclampsia

Oxidative stress is a disturbance in the oxidant-antioxidant balance and is caused by reactive oxygen species (ROS) -- negatively charged oxygen-containing molecules -- that includes superoxide, Hoffmann said. ROS can damage the cell's DNA, proteins, lipids and can affect the cell's signaling mechanisms. High levels of ROS are implicated in cardiovascular disease, cancer, and other diseases.

Cells produce an antioxidant, superoxide dismutase, to deal with the reactive oxygen species. Superoxide dismutase grabs the superoxide molecule and, over several steps, neutralizes it by converting it to water and oxygen.

Pre-eclampsia is not well understood because it is difficult to conduct experiments in high-risk pregnant women, and there haven't been good animal models for the condition, Hoffmann said. But the Iowa lab has begun using a mouse strain which has moderately elevated blood pressure, because women who have moderately elevated blood pressure have a five times greater chance of developing pre-eclampsia compared to women with normal blood pressure.

"We discovered these mice develop pregnancy-induced high blood pressure, proteinuria and placental abnormalities," Hoffmann said. The mice, like humans, are more likely to have impaired placental development and their fetuses are smaller, further making them a good model for the research.

Superoxide dismutase prevents pre-eclampsia

"In earlier studies, we discovered that there's a reduction in expression of one of the superoxide dismutase genes in the placenta of the model strain during early pregnancy. This leads to decreased levels of antioxidants, creating a potential for uncontrolled oxidant stress," Hoffmann said. "When we found less dismutase, we decided to try an antioxidant supplement to see if this would relieve the pre-eclampsia syndrome in the mice."

In this study, the researchers used an oral treatment of the antioxidant tempol, which mimics superoxide dismutase, to treat the superoxide imbalance. They started the antioxidant treatment before pregnancy and continued through pregnancy.

The tempol restored the oxidative balance in the placenta early in the pregnancy, Hoffmann said. The placentas of the tempol-treated mice and the weight of their fetuses were significantly improved compared to the mice that did not receive the treatment.

Tempol also reduced fetal deaths. This strain of mice typically "resorbs" about 30% of conceptuses, he said. But the tempol group resorbed only 15%.

In addition, the blood vessels in the placenta of the tempol-treated mice widened normally as they are supposed to. During a normal pregnancy, cells in the placenta interact with the mother's uterine blood vessels, making the vessels open wider to provide more blood supply to the fetus. The arteries of the non-tempol treated mice retained abnormally thick muscular walls, Hoffmann said.

Next step

The researchers will next perform studies to ensure the tempol does not have serious side effects that might interfere with the development of the fetuses and pups, Hoffmann said. Then, understanding exactly how reducing oxidative stress during pregnancy leads to improved outcomes will be a key component of future research.

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Funding: Research was funded by fellowships from the American Heart Association and from the Woodrow Wilson Fellowship Foundation in conjunction with Johnson & Johnson.

Editor's Note: For further information or to schedule an interview with a member of the research team, please contact Christine Guilfoy at the APS newsroom @ 415.905.1024 (March 31-April 5); 978.290.2400 (cell), 301.634.7253 (office), or cguilfoy@the-aps.org; or Mayer Resnick or 301.332.4402 (cell) or 301.634.7209 (office).

Go to http://www.faseb.org/meetings/eb2006/call/ and click on "Searchable Program Planner and Itinerary Builder to find the searchable online program for EB.

The American Physiological Society was founded in 1887 to foster basic and applied bioscience. The Bethesda, Maryland-based society has more than 10,000 members and publishes 14 peer-reviewed journals containing almost 4,000 articles annually.

APS provides a wide range of research, educational and career support and programming to further the contributions of physiology to understanding the mechanisms of diseased and healthy states. In May 2004, APS received the Presidential Award for Excellence in Science, Mathematics and Engineering Mentoring (PAESMEM).

Experimental Biology is an annual scientific meeting convened by the Federation of American Societies of Experimental Biology, including the American Physiological Society (APS) and other biomedical societies. The meeting features "nominated" lectures, symposia, research presentations, awards, a job placement center, and an exhibit of scientific equipment, supplies, and publications. This year's participating Societies are APS, American Association of Anatomists, American Society for Biochemistry and Molecular Biology, American Society for Investigative Pathology, American Society for Nutritional Sciences, and the American Society for Pharmacology and Experimental Therapeutics.


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