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 accessAbstract
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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Cites
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BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain
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Self-citationThe Phasor Approach to Fluorescence Lifetime Imaging Analysis
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Self-citationPerturbed Chloride Homeostasis and GABAergic Signaling in Human Temporal Lobe Epilepsy
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Cited by
Colloca, L., Ludman, T., Bouhassira, D., Baron, R., Dickenson, A. H., Yarnitsky, D., Freeman, R., Truini, A., Attal, N., Finnerup, N. B., et al. (2017) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2017.2 · Cited by 2,058
The GABA excitatory/inhibitory developmental sequence: A personal journey
Ben-Ari, Y. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.08.001 · Cited by 305
Advances in understanding nociception and neuropathic pain
St. John Smith, E. (2018) · Journal of Neurology · doi:10.1007/s00415-017-8641-6 · Cited by 282
Pain and Poppies: The Good, the Bad, and the Ugly of Opioid Analgesics
Trang, T., Al-Hasani, R., Salvemini, D., Salter, M. W., Gutstein, H., & Cahill, C. M. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2711-15.2015 · Cited by 273
The Cellular Mechanisms of Neuronal Swelling Underlying Cytotoxic Edema
Rungta, R. L., Choi, H. B., Tyson, J. R., Malik, A., Dissing-Olesen, L., Lin, P. J. C., Cain, S. M., Cullis, P. R., Snutch, T. P., & MacVicar, B. A. (2015) · Cell · doi:10.1016/j.cell.2015.03.029 · Cited by 255
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
- Published
- 2013-10-06
- Volume
- 19
- Issue
- 11
- Pages
- 1524-1528
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2004284432
- Cited by
- 356
- References
- 42
- FWCI
- 18.36
- Type
- journal article
- Language
- en
- Open access
- green
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- 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. (2013). Chloride extrusion enhancers as novel therapeutics for neurological diseases. Nature Medicine. https://doi.org/10.1038/nm.3356
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
