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Cited by 356

The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.

Chloride extrusion enhancers as novel therapeutics for neurological diseases

Open access
Gagnon, Martin, Bergeron, Marc J, Lavertu, Guillaume, Castonguay, Annie, Tripathy, Sasmita, Bonin, Robert P, Perez-Sanchez, Jimena, Boudreau, Dominic, Wang, Bin, Dumas, Lionel, Valade, Isabelle, Bachand, Karine, Jacob-Wagner, Mariève, Tardif, Christian, Kianicka, Irenej, Isenring, Paul, Attardo, Giorgio, Coull, Jeffrey A M, De Koninck, Yves·2013·Nature Medicine
DOI 10.1038/nm.3356
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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 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 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.

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Metadata

Authors
Gagnon, M., Bergeron, M. J., Lavertu, G., Castonguay, A., Tripathy, S., Bonin, R. P., Perez-Sanchez, J., Boudreau, D., Wang, B., Dumas, L., Valade, I., Bachand, K., Jacob-Wagner, M., Tardif, C., Kianicka, I., Isenring, P., Attardo, G., Coull, J. A. M., & De Koninck, Y.
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2013-10-06
Volume
19
Issue
11
Pages
1524-1528
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.3356
OpenAlex
W2004284432
Cited by
356
References
42
FWCI
18.36
Type
journal article
Language
en
Open access
green

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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

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