Hypoxic-ischemic encephalopathy [HIE] represents the most common acquired pathology associated with neonatal
seizures. HIE-associated neonatal
seizures are often difficult to control, due to their refractoriness to traditional anti-seizure agents. Developmentally regulated
chloride gradients during early development make the neonatal brain more seizure-susceptible by depolarizing GABAAR-mediated currents, and therefore hindering inhibition by conventional anti-seizure drugs such as
phenobarbital [PB] and
benzodiazepines. Pharmaco-modulation of
chloride co-transporters has become a current field of research in treating refractory neonatal
seizures, and the basis of two clinical trials [NCT01434225; NCT00380531]. However, the recent termination of NEMO study [NCT01434225] on
bumetanide, an NKCC1 antagonist, suggests that clinical utilization of
bumetanide as an adjunct to treat neonatal
seizures with PB may not be a viable option. Hence, re-evaluation of
bumetanide as an adjunct through pre-clinical studies is warranted. Additionally, the model-specific variability in the efficacy of
bumetanide in the pre-clinical models of neonatal
seizures highlights the differential consequences of insults used to induce
seizures in each pre-clinical model as worth exploration. Injury itself can significantly alter the function of
chloride co-transporters, and therefore the efficacy of anti-seizure agents that follow.