ArticleBrain : a journal of neurology2022
Inhibiting with-no-lysine kinases enhances K+/Cl- cotransporter 2 activity and limits status epilepticus.
Article in Brain : a journal of neurology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- WNK-SPAK/OSR1 signaling pathway facilitates ictal activity via reduced neuronal chloride extrusion rate.bioRxiv : the preprint server for biology · 2026Article
- Bridging the Gap: Harnessing Phytochemical-Loaded Nanocarriers for Enhanced Epilepsy Treatment.Molecular neurobiology · 2026Review
- GABACellular and molecular neurobiology · 2026Review
- Article
- Status epilepticus: Updates on mechanisms and treatments.Epilepsia open · 2025Review
- Bilirubin Targeting WNK1 to Alleviate NLRP3-Mediated Neuroinflammation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Inflammation and vasopressin hypersecretion in aging.Frontiers in endocrinology · 2025Review
- Article
- The brain-specific kinase LMTK3 regulates neuronal excitability by decreasing KCC2-dependent neuronal CliScience · 2024Article
- Compound 350: A New Hope for Individuals with Drug-resistant Epilepsy.Annals of neurosciences · 2024Article
- Targeted sonogenetic modulation of GABAergic interneurons in the hippocampal CA1 region in status epilepticus.Theranostics · 2024Article
- Neuronal KActa pharmacologica Sinica · 2024Review
- Uncovering novel KCC2 regulatory motifs through a comprehensive transposon-based mutant library.Frontiers in molecular neuroscience · 2024Article
- Development of KCC2 therapeutics to treat neurological disorders.Frontiers in molecular neuroscience · 2024Article
- The role ofJournal of pharmaceutical analysis · 2023Review
- Cell-specific NFIA upregulation promotes epileptogenesis by TRPV4-mediated astrocyte reactivity.Journal of neuroinflammation · 2023Article
- Treatment of status epilepticus: Physiology, pharmacology, and future directions.Epilepsia open · 2023Article
- Direct activation of KCC2 arrests benzodiazepine refractory status epilepticus and limits the subsequent neuronal injury in mice.Cell reports. Medicine · 2023Article
- Maternal taurine as a modulator of ClFrontiers in cellular neuroscience · 2023Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
First-in-line benzodiazepine treatment fails to terminate seizures in about 30% of epilepsy patients, highlighting a need for novel anti-seizure strategies. It is emerging that impaired K+/Cl- cotransporter 2 (KCC2) activity leads to deficits in GABAergic inhibition and increased seizure vulnerability in patients. In neurons, the with-no-lysine (WNK) kinase-STE20/SPS1-related proline/alanine-rich (SPAK) kinase signalling pathway inhibits KCC2 activity via T1007 phosphorylation. Here, we exploit the selective WNK kinase inhibitor WNK463 to test the effects of pharmacological WNK inhibition on KCC2 function, GABAergic inhibition, and epileptiform activity. Immunoprecipitation and western blotting analysis revealed that WNK463 reduces KCC2-T1007 phosphorylation in vitro and in vivo. Using patch-clamp recordings in primary rat neurons, we further observed that WNK463 hyperpolarized the Cl- reversal potential, and enhanced KCC2-mediated Cl- extrusion. In the 4-aminopyridine slice model of acute seizures, WNK463 administration reduced the frequency and number of seizure-like events. In vivo, C57BL/6 mice that received intrahippocampal WNK463 experienced delayed onset of kainic acid-induced status epilepticus, less epileptiform EEG activity, and did not develop pharmaco-resistance to diazepam. Our findings demonstrate that acute WNK463 treatment potentiates KCC2 activity in neurons and limits seizure burden in two well-established models of seizures and epilepsy. In summary, our work suggests that agents which act to increase KCC2 activity may be useful adjunct therapeutics to alleviate diazepam-resistant status epilepticus.
Indexed as
Identifiers
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.