ArticleNature medicine2013
Chloride extrusion enhancers as novel therapeutics for neurological diseases.
Article in Nature medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 197 papers.
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.
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Who cites it
197 citing papers in PubMed, 344 citations in OpenAlex.
- Regulated degradation of KCC2, a potassium-chloride co-transporter required for synaptic transmission and neurodevelopment.Channels (Austin, Tex.) · 2026Review
- Targeting Spinal Dorsal Horn Sensitisation in Chronic Pain: Mechanisms and Translational Strategies.Neuroscience bulletin · 2026Review
- Glial cells in neuropathic pain.Physiological reviews · 2026Review
- Advancing the Paradigm of Temporal Lobe Epilepsy as a Network Disease: The Promise of Biomarkers and Targeted Disease Modification.International journal of molecular sciences · 2026Review
- WNK-SPAK/OSR1 signaling pathway facilitates ictal activity via reduced neuronal chloride extrusion rate.bioRxiv : the preprint server for biology · 2026Article
- Solute carrier membrane transporters: emerging targets in CNS disorders.Nature reviews. Drug discovery · 2026Review
- Restoration of gamma-aminobutyric acid homeostasis: A novel approach to alleviating central nervous system injury-associated immunodepression syndrome.Neural regeneration research · 2026Article
- Acute stress induces circuit-specific alterations in mesolimbic and nigrostriatal inhibitory transmission and potentiates operant learning.bioRxiv : the preprint server for biology · 2026Article
- Spinal Processing of Spatiotemporally Diverse Tactile Stimuli: Computational Insights into Allodynia and Spinal Cord Stimulation.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Mismatch negativity-like responses in nitroglycerin-elicited migraine model.Scientific reports · 2026Article
- Enhancing KCC2 function reduces interictal activity and prevents seizures in temporal lobe epilepsy.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- KCC2 Dysfunction Mediated by Microglial BDNF/TrkB Signaling Exacerbates Early Post-Stroke Seizure Susceptibility.CNS neuroscience & therapeutics · 2026Article
- Article
- When the gatekeeper falls: developmental vulnerability of the thalamic reticular nucleus in neonatal and pediatric hypoxic-ischemic brain injury.Frontiers in systems neuroscience · 2026Review
- Dynamic changes in chloride homeostasis coordinate midbrain inhibitory network activity during reward learning.Nature communications · 2025Article
- Harnessing theta-gamma coupled brainwaves using ultrasound for spinal astrocyte revitalization and sustained neuropathic pain relief in mice.Nature communications · 2025Article
- Allosteric modulation of the solute carrier transporter SLC39A8 potentiates manganese and cadmium uptake.The Journal of clinical investigation · 2025Article
- Article
- AAV9-mediated KCC2 upregulation enhances functional recovery following cervical spinal cord injury.Communications biology · 2025Article
- KCC2 enhancers normalize reflex responses and improve locomotor function after chronic spinal cord injury.The Journal of physiology · 2025Article
137 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
19 authors at 2 institutions in 1 country.
Funding
Abstract
The K(+)-Cl(-) cotransporter KCC2 is responsible for maintaining low Cl(-) concentration in neurons of the central nervous system (CNS), which is essential for postsynaptic inhibition through GABA(A) and glycine receptors. Although no CNS disorders have been associated with KCC2 mutations, loss of activity of this transporter has emerged as a key mechanism underlying several neurological and psychiatric disorders, including epilepsy, motor spasticity, stress, anxiety, schizophrenia, morphine-induced hyperalgesia and chronic pain. Recent reports indicate that enhancing KCC2 activity may be the favored therapeutic strategy to restore inhibition and normal function in pathological conditions involving impaired Cl(-) transport. We designed an assay for high-throughput screening that led to the identification of KCC2 activators that reduce intracellular chloride concentration ([Cl(-)]i). Optimization of a first-in-class arylmethylidine family of compounds resulted in a KCC2-selective analog (CLP257) that lowers [Cl(-)]i. CLP257 restored impaired Cl(-) transport in neurons with diminished KCC2 activity. The compound rescued KCC2 plasma membrane expression, renormalized stimulus-evoked responses in spinal nociceptive pathways sensitized after nerve injury and alleviated hypersensitivity in a rat model of neuropathic pain. Oral efficacy for analgesia equivalent to that of pregabalin but without motor impairment was achievable with a CLP257 prodrug. These results validate KCC2 as a druggable target for CNS diseases.
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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.