A diuretic drug called bumetanide may serendipitously help treat seizures in newborns, which are difficult to control with existing anticonvulsants, according to a study in the November Nature Medicine. The study findings could lead to clinical trials of bumetanide in newborns, whose immature, rapidly-developing brains are especially vulnerable to seizures. Newborns' seizures can cause long-term neurologic impairments and a tendency toward seizures later in life.
Conventional anticonvulsants -- phenobarbital and benzodiazepines -- are ineffective in newborns because their brains are biochemically different from adult brains, says neurologist Frances Jensen, MD, of Children's Hospital Boston, a senior investigator on the study. Jensen's team, led by postdoctoral fellow Delia Talos, PhD, collaborated with Kevin Staley and colleagues at the University of Colorado Health Sciences Center to find a treatment for seizures that would work in newborns.
The researchers knew that conventional anticonvulsants work by mimicking the action of GABA, a natural inhibitory chemical in the brain, by activating GABA receptors on the surface of brain cells. In adult nerve cells, GABA activation opens up channels that allow chloride to move into the cell. The cell thereby acquires a negative charge and becomes less excitable, inhibiting seizure activity. But in newborns, chloride is already high, and therefore activating GABA receptors causes chloride to move out of nerve cells, creating a paradoxical excitatory reaction that may actually exacerbate seizures.
To better understand this paradox, the researchers focused on two molecules that regulate cellular chloride levels: KCC2, which transports chloride out of cells, and NKCC1, which brings chloride in. Previous studies in rats had shown that adult nerve cells mostly have KCC2, making their chloride concentrations lower inside than outside. Thus, when GABA receptors are activated, chloride tends to come in, with an inhibitory effect. In newborn rats, the situation is reversed: their nerve cells mostly have NKCC1, so chloride is actively transported inside, making initial chloride concentrations very high. As a result, GABA activation causes chloride to exit the cell, with an excitatory effect.
To see if the same pattern applies in humans, Talos and colleagues at Children's Hospital Boston examined NKCC1 and KCC2 levels in brain tissue from children who had died, ranging from second-trimester fetuses to preschool-age children. Just as in rats, NKCC1 levels were high during the fetal and newborn periods, peaking one week after birth, but fell during the first year of life, approaching the low levels found in adults. Also as in rats, KCC2 levels were initially low, but rose over the first year of life.
"We found that NKCC1 is expressed unopposed in the immature brain," says Jensen. "We thought that perhaps if we blocked its inward transfer of chloride, we could get immature neurons to act like older neurons and give GABA a chance to do what it's supposed to do."
The researchers knew that the diuretic bumetanide inhibits NKCC1 activity in the kidney, and reasoned that the drug might have a similar effect in the brain, lowering chloride levels and making nerve cells responsive to GABA activation. Staley and colleagues in Colorado conducted a trial in baby rats and found that bumetanide indeed inhibited seizure activity, while phenobarbital, as in humans, worked poorly.
The study's findings are in keeping with epidemiologic studies finding that adults taking diuretics for other reasons are less likely to have seizures. Jensen's group has begun discussions about launching a clinical trial of bumetanide in newborns. Although the drug is FDA-approved and has been used in newborns for other indications, a number of safety questions will first need to be addressed before a trial can proceed.
Last year, Jensen's lab found that another FDA-approved drug, topiramate, may prevent long-term seizure disorders in newborns who suffer seizures due to oxygen starvation. This drug acts by blocking another receptor, known as the AMPA glutamate receptor, which is much more abundant in newborns' brains than adult brains (see http://www.childrenshospital.org/newsroom/Site1339/mainpageS1339P1sublevel86.html). Like bumetamide, topiramate targets proteins that are uniquely expressed in the neonatal brain.
"As we learn more about age-specific brain mechanisms, we can develop novel therapies for newborn seizures, but in the meantime, there may be things already on the shelf that we can use," Jensen says.
The current study was funded by the National Institute of Neurological Disorders and Stroke and the Hearst Foundation.
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, nine members of the Institute of Medicine and 10 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 347-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: http://www.childrenshospital.org/research/.
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