{ "labelLang" : "hun", "responseDate" : "2024-03-28 21:18", "content" : { "otype" : "JournalArticle", "mtid" : 32881911, "status" : "VALIDATED", "published" : true, "comment" : "Department of Neurology, Duke University Medical Center, Durham, NC, United States \n Department of Anesthesiology (Center for Translational Pain Medicine), Duke University Medical Center, Durham, NC, United States \n Department of Neurobiology & Behavior, Institute for Memory Impairments and Neurological Disorders (iMIND), Center for the Neurobiology of Learning and Memory, University of California at Irvine, Irvine, CA, United States \n Department of Neurobiology, Duke University Medical Center, Durham, NC, United States \n Duke Neurology Clinics for Headache, Head-Pain and Trigeminal Sensory Disorders, Duke University Medical Center, Durham, NC, United States \n Duke Anesthesiology Clinics for Innovative Pain Therapy, Duke University Medical Center, Durham, NC, United States \n Cited By :11 \n Export Date: 8 June 2023 \n Correspondence Address: Yeo, M.; Department of Neurology, United States; email: myeo@duke.edu \n Correspondence Address: Chen, Y.; Department of Neurology, United States; email: yong.chen@duke.edu \n Correspondence Address: Liedtke, W.; Department of Neurology, United States; email: wolfgang.liedtke@regeneron.com \n Correspondence Address: Ji, R.-R.; Department of Anesthesiology (Center for Translational Pain Medicine), United States; email: ru-rong.ji@duke.edu \n Chemicals/CAS: 4 aminobutyric acid, 28805-76-7, 56-12-2; glycogen synthase kinase 3alpha; glycogen synthase kinase 3beta; kenpaullone, 142273-20-9; Analgesics; Benzazepines; Catenins; delta catenin; gamma-Aminobutyric Acid; Glycogen Synthase Kinase 3 beta; Indoles; kenpaullone; Symporters; Transcription Factors \n Funding details: National Institutes of Health, NIH, AG056850 \n Funding details: National Institute of Neurological Disorders and Stroke, NINDS, NS066307 \n Funding details: National Institute of Dental and Craniofacial Research, NIDCR, R01DE027454 \n Funding text 1: Invaluable comments on the manuscript were provided by Duke University colleagues Drs. James McNamara, Albert LaSpada, Nicole Calakos, Rochelle Schwartz-Bloom and Sidney Simon. We appreciate scientific editing of the manuscript by Dr. David Hauss (Regeneron). Viral DNA was packaged by the Duke Neurotransgenesis Viral Vector Core, lead-scientist Dr. Boris Kantor. Phospho-proteomics and DARTS analysis were conducted with the expert help of the Duke Proteomics Core Facility, Director Dr. M. Arthur Mosely and Lead-Scientist Dr. Erik Soderblom. KCC2 protein abundance microcapillary assays were carried out by Raybiotech (Norcross, GA). In terms of funding, this work was supported by NIH grants to W.L. (NS066307), Y.C. (DE027454), J.B. 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Here the authors identify from a screen of cancer drugs a kinase-inhibitor, kenpaullone, as an enhancer of Kcc2/KCC2 gene expression and show that it (i) alleviates pain like behaviour in animal models, (ii) repairs neural-circuit disrupting elevated chloride in pain relay neurons in the dorsal spinal cord.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. 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