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 GABAA 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 pain1,2,3,4,5,6,7,8,9. 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− transport10,11,12. 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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This work was supported by grants from the Canadian Institutes for Health Research and the Krembil Foundation to Y.D.K., a fellowship from the Savoy Foundation to M.J.B. and the Fonds de la recherche en santé du Québec Chercheur National Program to Y.D.K. We thank T. Kuner, University of Heidelberg, for the generous gift of the Clomeleon plasmid.
The authors declare no competing financial interests.
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Gagnon, M., Bergeron, M., Lavertu, G. et al. Chloride extrusion enhancers as novel therapeutics for neurological diseases. Nat Med 19, 1524–1528 (2013). https://doi.org/10.1038/nm.3356
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