Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission

• Published in: Nature communications 2021-10, Vol.12 (1), p.6208-16, Article 6208
• Main Authors: Yeo, Michele, Chen, Yong, Jiang, Changyu, Chen, Gang, Wang, Kaiyuan, Chandra, Sharat, Bortsov, Andrey, Lioudyno, Maria, Zeng, Qian, Wang, Peng, Wang, Zilong, Busciglio, Jorge, Ji, Ru-Rong, Liedtke, Wolfgang
• Format: Article
• Language: English
• Subjects: 13/95; 38; 38/5; 38/88; 49; 631/154/1435; 631/378/1689/2610; 64/110; 96; Action Potentials - drug effects; Analgesia; Analgesics - pharmacology; Analgesics - therapeutic use; Animal behavior; Animal models; Animals; Benzazepines - pharmacology; Benzazepines - therapeutic use; Bone cancer; Cancer; Cancer Pain - drug therapy; Catenin; Catenins - genetics; Catenins - metabolism; Cells, Cultured; Central nervous system; Chloride; Chloride ions; Chlorides; Chronic pain; Circuits; Delta Catenin; Dorsal horn; Drug Evaluation, Preclinical; Drug Repositioning; Drugs; Enzyme inhibitors; Extrusion; gamma-Aminobutyric Acid - metabolism; Gene expression; Gene Expression Regulation - drug effects; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Humanities and Social Sciences; Humans; Indoles - pharmacology; Indoles - therapeutic use; Injury prevention; Kinases; Mice; multidisciplinary; Neuralgia - drug therapy; Neurons; Neurons - drug effects; Neurons - metabolism; Neuroprotection; Neurotransmission; Overexpression; Pain; Pain perception; Phosphorylation; Potassium-chloride cotransporter; Rats; Science; Science (multidisciplinary); Spinal cord; Spinal Cord Dorsal Horn - drug effects; Spinal Cord Dorsal Horn - metabolism; Spinal Cord Dorsal Horn - pathology; Symporters - genetics; Symporters - metabolism; Synaptic Transmission - drug effects; Transcription Factors - metabolism; Vertebrates; γ-Aminobutyric acid
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-26270-3

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. Lack of expression and function of chloride ion-extruding transporter KCC2 in central neurons, a consequence of various forms of neural injury, is strongly suggested to contribute to chronic pain. 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.