Arthritis Drug Shows Promise for Reducing Brain Hemorrhage in Premature Babies

NINDS, Jan 10, 2008

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.

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