injury and seizures in newborns
drug may block damage at its source
A difficult birth or complications in late pregnancy can choke
off blood and oxygen flow to the baby's developing brain.
This hypoxia-ischemia can cause brain injury and set the stage
for long-term neurologic abnormalities and conditions such as
cerebral palsy and epilepsy, for which there is no good treatment.
For years, researchers at Children's Hospital Boston have
probed the biology of hypoxic-ischemic brain injury, and their
discoveries may eventually provide the basis for a protective
therapy for newborns.
Hypoxia-ischemia causes the brain's major excitatory neurotransmitter,
glutamate, to accumulate in excess; the chemical pools around
neurons and essentially excites them to death. “Both term
and pre-term newborns are highly susceptible to this excitotoxicity,”
Jensen, MD, of the Department of Neurology and Program
in Neuroscience at Children's, “because their rapidly
developing brains have far more glutamate receptors than adult
Dr. Jensen decided that the glutamate receptor might be a good
target for therapy. In two recent NIH-funded studies, her team
showed that an existing anticonvulsant drug, topiramate, can prevent
long-term neurologic damage from hypoxia-ischemia in animals by
blocking the AMPA receptor, a type of glutamate receptor.
One study looked at periventricular leukomalacia (PVL), an injury
to cerebral white matter that underlies cerebral palsy. Most common
in preterm infants, PVL is thought to be caused by excitotoxic
damage to oligodendrocytes, which are myelin-producing cells whose
injury leads to neuromotor problems.
In the May 5 issue of The
Journal of Neuroscience, the researchers first showed
that developing human oligodendrocytes have the most AMPA glutamate
receptors at 23 to 32 weeks' gestation, the time of greatest risk
for PVL. They then demonstrated that rats given topiramate immediately
after a hypoxic-ischemic event were protected from oligodendrocyte
injury and had fewer neuromotor abnormalities than untreated rats.
Normal oligodendrocyte development was unaffected.
“The finding that treatment prevented injury when given
after the insult is tremendously significant,”
says Dr. Jensen. “Many studies of injury protection have
demonstrated an effect of pretreatment, a more clinically
limited paradigm. If closely monitored, a premature infant can
feasibly begin treatment within a few minutes after an insult.”
A second study, published in the June Epilepsia,
found evidence that topiramate can prevent epilepsy, again by
blocking AMPA glutamate receptors. Dr. Jensen and colleagues studied
a rat model of hypoxic encephalopathy, the most common cause of
seizures in newborns. Babies with hypoxia-induced seizures can
later develop epilepsy, often associated with neuromotor deficits.
There is no effective intervention; adult seizure medications
don't work in more severe cases.
Dr. Jensen's group found that rats treated with topiramate
for 48 hours after a hypoxia-induced seizure were less susceptible
to seizure-induced damage later in life. “Appropriate intervention
after early-life seizures may prevent the development of epilepsy
and neurocognitive deficits, as well as brain injury associated
with repeated seizures in adulthood,” Dr. Jensen says. “Again,
pretreatment is not always practical, so post-seizure treatment
would represent a therapeutic advance.”
Dr. Jensen's findings suggest that topiramate may be useful
for both premature infants at risk for PVL and newborns with seizures
due to hypoxia. The drug is FDA-approved for adults and children
over age 3, but its safety in younger children isn't known.
Children's is starting a pharmacokinetic study of topiramate
in infants, which should shed light on the safety question. In
the meantime, Dr. Jensen is looking for new therapeutic targets.
“By further studying mechanisms of injury in the newborn
brain, we hope to continue to elucidate new therapies for this
age group,” she says.