Neonatal
seizures caused by perinatal
asphyxia and
hypoxic-ischemic encephalopathy can be refractory to conventional
anticonvulsants. This may be due to the depolarizing effects of
gamma-aminobutyric acid (
GABA) achieved by the activity of the Na(+)-K(+)-2Cl(-)
cotransporter (NKCC1). The aim of this study is to evaluate the long-term effects of
bumetanide, a NKCC1 inhibitor, on hippocampal neurogenesis and seizure susceptibility in
hypoxia-induced neonatal seizure model. Wistar rats were subjected to
hypoxia-induced neonatal
seizures at postnatal day 10 (P10). Following acute
seizures, the rats were treated with
intraperitoneal injection (i.p.) of
bumetanide at a dose of 0.5mg/kg for 3 weeks. In later adulthood,
hypoxia-induced
seizures increased the number of newborn dentate gyrus cells (DGCs), promoted mossy fiber sprouting (MFS) and reduced the apical dendritic complexity of newborn DGCs 1 month after the insults. In addition, these
seizures resulted in long-lasting consequences, such as spontaneous electroencephalography (EEG)
seizures, though spatial learning impairments were not seen.
Bumetanide treatments significantly enhanced cell proliferation and dendritic development of newborn DGCs after neonatal
seizures, accompanied by the decreased seizure activity. However, systemic administration of
bumetanide resulted in much lower brain concentrations, and was incompatible with NKCC1 inhibition in blood-brain barrier (BBB)-protected brain tissue. Our results suggested that
bumetanide might have long-term effects in suppressing seizure activity, and altering the neurogenesis after neonatal
seizures. These effects of
bumetanide may be mediated by the targets outside the BBB-protected central nerve system (CNS) or CNS-located target(s) other than NKCC1.