Can an Alzheimer's drug help prevent cerebral palsy?
Preclinical study finds memantine to reverse hypoxic brain injury after birth
June 24, 2008
A drug used to treat Alzheimer's patients may reduce the brain damage that afflicts many premature infants, report researchers from Children's Hospital Boston. Although the study involved a rat model of cerebral palsy and brain injury in premature infants, the findings may provide the basis for a protective therapy for preterm babies. No such therapy currently exists.
An increase in multiple gestations has led to more premature, very-low-birthweight infants. While more of these babies are surviving, up to 35 percent are left with brain injuries leading to cerebral palsy and cognitive/behavioral deficits. During the past decade, researchers at Children's have documented a complex web of insults sustained by premature babies' brain cells, particularly the cells that form the brain's white matter, known as oligodendrocytes. Hypoxia-ischemia, a compromise of the brain's blood and oxygen supply, is often the trigger. Not only are preemies at high risk for hypoxia-ischemia, but their immature oligodendrocytes are exquisitely vulnerable to hypoxic-ischemic injury because of the developing cells' unique biology.
Now, in the June 25 issue of the Journal of Neuroscience, Frances Jensen, MD, Simon Manning, MD, Delia Talos, MD, and colleagues in Children's Department of Neurology and Neurobiology Program demonstrate that the Alzheimer's drug memantine can reduce white-matter injury after a hypoxic-ischemic episode. The drug, marketed in the U.S. as Namenda®, acts by blocking a type of glutamate receptor in the brain known as the NMDA receptor.
Jensen and colleagues first showed that the immature oligodendrocytes of preterm infants make NMDA receptors at the time in development when they are most vulnerable to white-matter injury, mirroring the pattern seen in rats. As a result, after a hypoxic-ischemic insult, the neurotransmitter glutamate accumulates in brain tissue and can cause over-activation of NMDA receptors, leading to a pattern of white-matter injury known as periventricular leukomalacia (PVL). But when rats were treated with memantine after a hypoxic-ischemic insult, this over-activation did not occur and white-matter injury was significantly reduced. The normal development of oligodendrocytes appeared to be unaffected.
"The premature brain is not just a 'small' adult brain -- it is physiologically different and thus contains unique targets for therapy," says Jensen, the study's senior investigator. "The NMDA receptor in white matter may be one of those targets. We tested this target in the animal model, and we also show that it is present in the premature human brain."
The next step is to evaluate potential safety risks of memantine in premature newborns. Eventually, Jensen and colleagues hope to conduct a clinical trial in premature infants at risk for PVL.
Children's Hospital Boston participated in the development of memantine for Alzheimer's and certain other progressive neurologic diseases during the 1990s (Stuart Lipton, MD, PhD, then at Children's now at the Burnham Institute for Medical Research, is a co-inventor on the patent). Memantine is marketed in the U.S. under the brand name Namenda (Forest Laboratories, Inc.).
In 2004, Jensen showed that another type of glutamate receptor, known as the AMPA receptor, is also abundant in developing oligodendrocytes, and that an existing drug for epilepsy, topiramate, can block AMPA receptor activation and reduce the risk for PVL. Jensen hopes to conduct clinical trials of topiramate in newborns and infants, since it is currently FDA-approved only for adults and children over age 3. Since it is only available in oral form, researchers are working on developing an intravenous formulation that could be used in premature infants.
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 397-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: www.childrenshospital.org/newsroom.
Frances Jensen, MD