An existing drug already approved by the FDA may protect newborns from brain injury and long-term neurologic problems caused by excitotoxicity, or over-activation of neurons, report two NIH-funded studies from Children's Hospital Boston
. The drug, topiramate, is currently approved to control seizures in adults and in children over age 3, but the findings may provide the basis for a protective therapy that could be given to babies immediately after traumatic birth events that compromise the brain's blood and oxygen supply. Such events can cause long-term neurologic abnormalities that underlie serious conditions like cerebral palsy and epilepsy. Premature infants, who are surviving in greater numbers, are especially vulnerable to excitotoxicity.
When the brain's blood and oxygen supply are compromised, a condition known as hypoxia-ischemia, the chemical glutamate accumulates in brain tissues. Glutamate binds to receptors on neurons and over-activates them, causing the brain cells to die. The Children's Hospital researchers, led by Dr. Frances Jensen, have found that the neurons of premature infants and other newborns have more glutamate receptors than the adult brain, making them very vulnerable to excitotoxic brain injury from hypoxia-ischemia. In two studies, they investigated whether compounds that block a certain type of glutamate receptor, known as AMPA, can dampen the harmful effects of excitotoxicity in the immature brain.
The first study, published in the May 5 issue of The Journal of Neuroscience, examined a type of brain damage called periventricular leukomalacia (PVL) that underlies cerebral palsy. PVL is most common in the preterm infant and is thought to be caused by excitotoxic damage to oligodendrocytes, cells that produce a substance called myelin. Myelin insulates neurons and enhances signal transmission; without it, neurons cannot communicate efficiently and neuromotor problems result.
In the study, Jensen, Dr. Pamela Follett and colleagues first showed that developing human oligodendrocytes have peak numbers of AMPA glutamate receptors at 23-32 weeks' gestation, the time of greatest risk for PVL. They then tested topiramate, which blocks AMPA glutamate receptors, in a rodent model for PVL. When topiramate was given immediately after a hypoxic-ischemic event, rats were protected from oligodendrocyte injury and showed fewer neuromotor abnormalities than the untreated rats. The researchers went on to show that topiramate does not affect the normal development of oligodendrocytes.
"The finding that treatment with a drug prevents injury when given after the insult is tremendously significant," says Jensen, of the Department of Neurology and Program in Neuroscience at Children's. "Many studies of injury protection have demonstrated an effect of pretreatment, a much more clinically limited paradigm. Because premature infants are typically maintained in a continuously monitored, intensive care setting, it's feasible to commence treatment even within a few minutes after an insult."
A second study, published in the June issue of Epilepsia, found that topiramate may also be useful in preventing epilepsy, again by blocking AMPA glutamate receptors. Jensen and her team, including Dr. Sookyong Koh, investigated a condition called hypoxic encephalopathy, the most common cause of seizures in newborns. Infants with neonatal seizures due to hypoxia-ischemia can develop epilepsy, often in association with neuromotor deficits. "Currently, there is no effective intervention for these newborns to prevent brain injury and long-term brain abnormalities," notes Jensen.
Animal studies have suggested that seizures in the immature brain can cause permanent changes making the brain more prone to seizures. "In a rat model, we have shown that early life seizures induced by hypoxic encephalopathy increase susceptibility to seizure-induced neuronal injury later in life," says Jensen. "We also know that this early seizure activity appears to be dependent on the AMPA subtype of glutamate receptors. We therefore examined whether topiramate might curb the excitotoxicity associated with neonatal seizures."
Rats treated with topiramate prior to perinatal hypoxia-induced seizures indeed were less susceptible to seizures later in life. More significantly, topiramate given for 48 hours after hypoxia-induced seizures also reduced susceptibility to seizure-induced damage later in life. "In human babies, pretreatment is not always clinically practical, so post-seizure treatment would represent a therapeutic advance," says Jensen. "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."
While therapeutic doses of the drug do not appear to alter normal brain development in the rat, topiramate's safety in children under age three has not been studied.
Taken together, results from these studies suggest that topiramate treatment may be useful for premature infants at risk for PVL and for neonatal seizures due to perinatal hypoxia.
"By further studying unique mechanisms of injury in the newborn brain, we hope to continue to elucidate new therapies for use in this age group," says Jensen. "However, since agents already approved for use in adults are also effective, our results indicate that a clinical trial should be considered to determine topiramate's safety and efficacy in newborns."