Gagnon M.,University of Québec |
Gagnon M.,Laval University |
Bergeron M.J.,University of Québec |
Bergeron M.J.,Laval University |
And 25 more authors.
Nature Medicine | Year: 2013
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. © 2013 Nature America, Inc.