ArticleNature medicine2005
NKCC1 transporter facilitates seizures in the developing brain.
Article in Nature medicine, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00830531 (Pilot Study of Bumetanide for Newborn Seizures), which is not on this map. Cited by 455 papers, 4 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Pilot Study of Bumetanide for Newborn Seizures: A Phase I Study of Pharmacokinetics and Safety of Bumetanide for Neonatal Seizures
Who cites it
455 citing papers in PubMed, 4 syntheses or guidelines pooled it, 965 citations in OpenAlex.
- Anti-seizure medications for neonates with seizures.The Cochrane database of systematic reviews · 2023Pooled it
- Mechanisms Underlying Aquaporin-4 Subcellular Mislocalization in Epilepsy.Frontiers in cellular neuroscience · 2022Pooled it
- Treating the symptom or treating the disease in neonatal seizures: a systematic review of the literature.Italian journal of pediatrics · 2021Pooled it
- Neurosteroids and Seizure Activity.Frontiers in endocrinology · 2020Pooled it
- A Phase III Study of Bumetanide Oral Liquid Formulation for the Treatment of Children and Adolescents Aged Between 7 and 17 Years with Autism Spectrum Disorder (SIGN 1 Trial): Participant Baseline Characteristics.Child psychiatry and human development · 2023Trial
- Clarifications regarding bumetanide for neonatal seizures.Epilepsia · 2022Trial
- A Pilot Randomized, Controlled, Double-Blind Trial of Bumetanide to Treat Neonatal Seizures.Annals of neurology · 2021Trial
- Epilepsy Mechanisms in Down Syndrome: Genetic and Pathophysiological Perspectives Across the Lifespan.Journal of clinical medicine · 2026Review
- WNK-SPAK/OSR1 signaling pathway facilitates ictal activity via reduced neuronal chloride extrusion rate.bioRxiv : the preprint server for biology · 2026Article
- Psychopharmacological Mechanisms of Antidepressant Withdrawal: Insights From Venlafaxine.Human psychopharmacology · 2026Review
- Chasing the ghost in the code: highlighting the mystery of a rare genetic condition.American journal of physiology. Cell physiology · 2026Review
- TRPV4 inhibition as a pharmacotherapy for post-hemorrhagic hydrocephalus.Fluids and barriers of the CNS · 2026Article
- Electrophysiologically Targeted Biopsies Reveal the Transcriptional Landscape of Focal Epilepsy.bioRxiv : the preprint server for biology · 2026Article
- Neonatal seizures and GABAergic drugs: Scylla and Charybdis?Epilepsia open · 2026Review
- Ablation of Unilateral Hippocampal GABAergic Neurons: A Novel Mouse Model of Mesial Temporal Lobe Epilepsy With Hippocampal Sclerosis.CNS neuroscience & therapeutics · 2026Article
- Association Between Genetically Proxied SLC12A2 Inhibition and Inflammatory Bowel Disease: A Mendelian Randomization Study.Biochemical genetics · 2026Article
- 4-Aminopyridine induced hyperpolarizing oscillations in pediatric human epileptic tissue are network-driven potassium currents that are abolished by activation of KCNQ2-5 (Kv7.2-Kv7.5) channels.Neurobiology of disease · 2026Article
- When the gatekeeper falls: developmental vulnerability of the thalamic reticular nucleus in neonatal and pediatric hypoxic-ischemic brain injury.Frontiers in systems neuroscience · 2026Review
- Treatment considerations for the management of neonatal onset seizures.The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG · 2025Article
- The First 30 Days Postnatal of the GABA Receptor: A Comprehensive Overview.Molecular neurobiology · 2025Review
395 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 1 country.
Funding
Abstract
During development, activation of Cl(-)-permeable GABA(A) receptors (GABA(A)-R) excites neurons as a result of elevated intracellular Cl(-) levels and a depolarized Cl(-) equilibrium potential (E(Cl)). GABA becomes inhibitory as net outward neuronal transport of Cl(-) develops in a caudal-rostral progression. In line with this caudal-rostral developmental pattern, GABAergic anticonvulsant compounds inhibit motor manifestations of neonatal seizures but not cortical seizure activity. The Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) facilitates the accumulation of Cl(-) in neurons. The NKCC1 blocker bumetanide shifted E(Cl) negative in immature neurons, suppressed epileptiform activity in hippocampal slices in vitro and attenuated electrographic seizures in neonatal rats in vivo. Bumetanide had no effect in the presence of the GABA(A)-R antagonist bicuculline, nor in brain slices from NKCC1-knockout mice. NKCC1 expression level versus expression of the Cl(-)-extruding transporter (KCC2) in human and rat cortex showed that Cl(-) transport in perinatal human cortex is as immature as in the rat. Our results provide evidence that NKCC1 facilitates seizures in the developing brain and indicate that bumetanide should be useful in the treatment of neonatal seizures.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.