ArticleNature communications2021
Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 32 citations in OpenAlex.
- Vascular smooth muscle cell-derived KIF13B inhibits proinflammatory responses to protect against atherosclerosis.The Journal of clinical investigation · 2026Article
- A patent review of cyclin-dependent kinase 5 (CDK5) inhibitors (1999-2025).Frontiers in bioengineering and biotechnology · 2026Review
- Mechanical cues as immunomodulators in neuroinflammation-driven spinal sensitization: analgesic mechanisms and therapeutic strategies.Frontiers in immunology · 2026Review
- Spinal KCC2 Mediates the Modulation Effect of HDAC2 on Bone Cancer Pain in Rats.Current cancer drug targets · 2026Article
- Neurological and hematological safety profiles of GSK-3β inhibitors: insights from multi-database pharmacovigilance and experimental validation.Frontiers in immunology · 2026Article
- AAV9-mediated KCC2 upregulation enhances functional recovery following cervical spinal cord injury.Communications biology · 2025Article
- SARS-CoV-2 infection of human cortical cells is influenced by the interaction between aneuploidy and biological sex: insights from a Down syndrome in vitro model.Acta neuropathologica · 2025Article
- Targeting GABA signaling in the tumor microenvironment: implications for immune cell regulation and immunotherapy resistance.Frontiers in immunology · 2025Review
- [Additional experience with medicinal treatment of trigeminal nerve pain].Schmerz (Berlin, Germany) · 2024Article
- Development of KCC2 therapeutics to treat neurological disorders.Frontiers in molecular neuroscience · 2024Article
- Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer's disease mutations.Brain : a journal of neurology · 2023Article
- KLF4 transcription factor in tumorigenesis.Cell death discovery · 2023Review
- Neuropathic pain: Mechanisms and therapeutic strategies.Frontiers in cell and developmental biology · 2023Review
- Neuropathic pain; what we know and what we should do about it.Frontiers in pain research (Lausanne, Switzerland) · 2023Review
- Glycogen Synthase Kinase 3β: A True Foe in Pancreatic Cancer.International journal of molecular sciences · 2022Review
- Ionic Plasticity: Common Mechanistic Underpinnings of Pathology in Spinal Cord Injury and the Brain.Cells · 2022Review
- Osteoporosis in Light of a New Mechanism Theory of Delayed Onset Muscle Soreness and Non-Contact Anterior Cruciate Ligament Injury.International journal of molecular sciences · 2022Article
- Spinal cord dorsal horn sensory gate in preclinical models of chemotherapy-induced painful neuropathy and contact dermatitis chronic itch becomes less leaky withFrontiers in molecular neuroscience · 2022Article
- Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma.Frontiers in molecular neuroscience · 2022Review
- Long March Toward Safe and Effective Analgesia by Enhancing Gene Expression ofFrontiers in molecular neuroscience · 2022Review
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
Inhibitory GABA-ergic neurotransmission is fundamental for the adult vertebrate central nervous system and requires low chloride concentration in neurons, maintained by KCC2, a neuroprotective ion transporter that extrudes intracellular neuronal chloride. To identify Kcc2 gene expression‑enhancing compounds, we screened 1057 cell growth-regulating compounds in cultured primary cortical neurons. We identified kenpaullone (KP), which enhanced Kcc2/KCC2 expression and function in cultured rodent and human neurons by inhibiting GSK3ß. KP effectively reduced pathologic pain-like behavior in mouse models of nerve injury and bone cancer. In a nerve-injury pain model, KP restored Kcc2 expression and GABA-evoked chloride reversal potential in the spinal cord dorsal horn. Delta-catenin, a phosphorylation-target of GSK3ß in neurons, activated the Kcc2 promoter via KAISO transcription factor. Transient spinal over-expression of delta-catenin mimicked KP analgesia. Our findings of a newly repurposed compound and a novel, genetically-encoded mechanism that each enhance Kcc2 gene expression enable us to re-normalize disrupted inhibitory neurotransmission through genetic re-programming.
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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.