Bumetanide for neonatal seizures: No light in the pharmacokinetic/dynamic tunnel.
NKCC1
animal models
bumetanide
hypoxic-ischemic encephalopathy
neonatal seizures
Journal
Epilepsia
ISSN: 1528-1167
Titre abrégé: Epilepsia
Pays: United States
ID NLM: 2983306R
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
11
04
2022
accepted:
12
04
2022
pubmed:
8
5
2022
medline:
15
7
2022
entrez:
7
5
2022
Statut:
ppublish
Résumé
In his editorial, Kevin Staley criticizes our recent work demonstrating the lack of effect of bumetanide in a novel model of neonatal seizures. The main points in our response are that (1) our work is on an asphyxia model, not one on "hypercarbia only"; (2) clinically relevant parenteral doses of bumetanide applied in vivo lead to concentrations in the brain parenchyma that are at least an order of magnitude lower than what would be sufficient to exert any direct effect-even a transient one-on neuronal functions, including neonatal seizures; and (3) moreover, bumetanide's molecular target in the brain is the Na-K-2Cl cotransporter NKCC1, which has vital functions in neurons, astrocytes, and oligodendrocytes as well as microglia. This would make it impossible even for highly brain-permeant NKCC1 blockers to specifically target depolarizing and excitatory actions of γ-aminobutyric acid in principal neurons of the brain, which is postulated as the rationale of clinical trials on neonatal seizures.
Identifiants
pubmed: 35524446
doi: 10.1111/epi.17279
pmc: PMC9545618
doi:
Substances chimiques
Sodium Potassium Chloride Symporter Inhibitors
0
Solute Carrier Family 12, Member 2
0
Bumetanide
0Y2S3XUQ5H
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1868-1873Informations de copyright
© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
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