Antioxidant Tempol Prevents
Pre-Eclampsia In Mice
SAN FRANCISCO (April 2, 2006) – 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
“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.
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 Donna Krupa or (703) 967-2751 (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.
