For release: Monday, August 27, 2007
A drug that is commonly used to reduce the pain of arthritis may eventually be used in pregnant women with preterm labor to lessen the risk of brain damage in very low birthweight babies, a new study suggests.
Premature infants, especially those born before 32 weeks of gestation and weighing under 1500 grams (about 3 pounds, 5 ounces), are at high risk of brain hemorrhages, or bleeding, that can lead to cerebral palsy, seizures, and other long-term problems. Brain hemorrhages affect about 12,000 premature infants each year in the United States. Most of these bleeds occur in a part of the brain called the germinal matrix, a structure near the brain ventricles where all the developing baby’s brain cells originate. This structure normally disappears by 36 weeks of gestation.
In the new study, led by Dr. Praveen Ballabh at New York Medical College-Westchester Medical Center in Valhalla, New York, and Dr. Maiken Nedergaard at the University of Rochester Medical Center in New York, researchers traced the high risk of germinal matrix hemorrhage to newly formed blood vessels in that part of the brain. Administering the drug celecoxib, which is commonly used to treat arthritis pain, reduced the proliferation of these blood vessels and substantially decreased the incidence of brain hemorrhage in an animal model. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the journal Nature Medicine.
The germinal matrix produces new neurons and glial cells that then migrate to other parts of the brain. Maintaining this activity requires a large amount of blood and oxygen, so the germinal matrix grows many temporary blood vessels to support the neuron development, Dr. Ballabh explains. This process of forming new blood vessels, called angiogenesis, is triggered by proteins called vascular endothelial growth factor (VEGF) and angiopoietin-2 (ANGPT-2).
Unfortunately, newly developed blood vessels in the germinal matrix are very fragile. When a baby is born before the germinal matrix disappears, the premature infant's unstable medical condition can cause fluctuations in blood pressure, which in turn can rupture the fragile germinal matrix blood vessels. Some hemorrhages are very small and cause few problems, but others cause severe brain damage.
In the new study, Dr. Ballabh and his colleagues examined autopsied human brain tissue from fetuses, premature infants, and full-term babies. They found that, in fetuses and premature infants, VEGF and ANGPT-2 were more abundant in the germinal matrix than in the brain's cortex and white matter. The amount of blood vessel proliferation was also much greater in the germinal matrix than in other areas. The proliferation decreased soon after birth. The researchers suspect that the increased blood oxygen after babies began to breathe air reduced the level of VEGF, halting the development of new blood vessels.
Dr. Ballabh reasoned that reducing the amount of VEGF and ANGPT-2 in the brain just prior to birth might temporarily stop the development of new blood vessels in the germinal matrix and make the brain less likely to bleed. The researchers tested this idea by giving pregnant rabbits either of two inhibitors of angiogenesis, celecoxib or another drug called ZD6474, for several days prior to birth. Both drugs reduced the level of VEGF and decreased the incidence and severity of brain hemorrhage in premature rabbit pups.
While both drugs appeared to be safe in pregnant rabbits, most of the pups born after ZD6474 treatment died 3 to 4 days after birth, Dr. Ballabh says. In contrast, the celecoxib-treated pups remained apparently healthy. Celecoxib is sometimes used to suppress preterm labor in women, and it has few known adverse effects.
The researchers are now planning additional studies to examine the safety and effectiveness of celecoxib and ZD6474 in animal models. These studies will examine whether the drugs affect neuron development, lung function, and other characteristics in newborn animals. The investigators will also try to determine the best dose of the medication to prevent brain hemorrhage without causing adverse effects. The doses of medication used in the initial study were quite large, so it is unclear whether smaller doses would be effective. If all goes well, Dr. Ballabh hopes to eventually begin a clinical trial to determine if treating women in preterm labor with celecoxib or a similar drug can prevent brain damage in premature babies.
The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
-By Natalie Frazin
Ballabh P, Xu H, Hu F, Braun A, Smith K, Rivera A, Lou N, Ungvari Z, Goldman SA, Csiszar A, Nedergaard M. “Angiogenic inhibition reduces germinal matrix hemorrhage.” Nature Medicine, April 2007, vol. 13, no. 4, pp. 477-485.
Last Modified August 27, 2007