Chloride extrusion enhancers as novel therapeutics for neurological diseases View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-10-06

AUTHORS

Martin Gagnon, Marc J. Bergeron, Guillaume Lavertu, Annie Castonguay, Sasmita Tripathy, Robert P. Bonin, Jimena Perez-Sanchez, Dominic Boudreau, Bin Wang, Lionel Dumas, Isabelle Valade, Karine Bachand, Mariève Jacob-Wagner, Christian Tardif, Irenej Kianicka, Paul Isenring, Giorgio Attardo, Jeffrey A.M. Coull, Yves De Koninck

ABSTRACT

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. More... »

PAGES

1524-1528

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nm.3356

DOI

http://dx.doi.org/10.1038/nm.3356

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1012088855

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24097188


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