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Austin J Cerebrovasc Dis Stroke. 2014;1(6). pii: 1026.

Pre-Clinical Models of Acquired Neonatal Seizures: Differential Effects of Injury on Function of Chloride Co-Transporters.

Author information

1
Neuroscience Laboratory, Hugo Moser Research Institute, USA.
2
Neuroscience Laboratory, Hugo Moser Research Institute, USA ; Department of Neurology, Johns Hopkins University, USA.

Abstract

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.

KEYWORDS:

Bumetanide; Chloride co-transporters; Hypoxic-ischemic encephalopathy (HIE); KCC2; NKCC1; Neonatal seizures

PMID:
25590049
PMCID:
PMC4290373

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