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."