title: Bumetanide reduces seizure progression and the development of pharmacoresistant status epilepticus.
abstract: OBJECTIVE
  We investigated the role of chloride homeostasis in seizure progression and development of pharmacoresistant status epilepticus (SE) by pharmacologically targeting the Na-K-Cl cotransporter (NKCC1) with bumetanide. We also investigated the ability of bumetanide to restore the efficacy of diazepam following SE.
  
  
  METHODS
  Kainic acid (KA)-induced SE in vivo and 0-Mg(2+) -induced seizure-like events (SLEs) in vitro were monitored using electroencephalography (EEG) recordings in freely moving adult male mice and extracellular field potential recordings in acute entorhinal cortex-hippocampus slices, respectively. The ability of bumetanide to decrease epileptiform activity and prevent the development of pharmacoresistance to diazepam following SE was evaluated.
  
  
  RESULTS
  Bumetanide treatment significantly reduced KA-induced ictal activity in vivo and SLEs in vitro. In addition, bumetanide restored the efficacy of diazepam in decreasing ictal activity following SE in both the in vivo and in vitro models.
  
  
  CONCLUSIONS
  Our data demonstrate an anticonvulsant effect of bumetanide on KA-induced seizures in adult mice, suggesting a role for chloride plasticity in seizure progression. These data also demonstrate that the erosion of inhibition during seizure progression could underlie the development of pharmacoresistant SE and implicate a role for chloride plasticity in this process.
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki, Finland.|Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, U.S.A.
authors.forename: Sudhir
authors.identifier: http://orcid.org/0000-0002-8586-0469
authors.initials: S
authors.lastname: Sivakumaran
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, U.S.A.
authors.forename: Jamie
authors.initials: J
authors.lastname: Maguire
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002034:Bumetanide / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D018450:Disease Progression; D000069279:Drug Resistant Epilepsy / Q000503:physiopathology*; D004569:Electroencephalography; D018728:Entorhinal Cortex / Q000187:drug effects* / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology*; D013226:Status Epilepticus / Q000503:physiopathology*
chemical_list: D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D049994:Sodium Potassium Chloride Symporter Inhibitors; D002034:Bumetanide; D003975:Diazepam; D007608:Kainic Acid
keywords: Chloride; Epilepsy; GABA; NKCC1; Pharmacoresistance; Status epilepticus