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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(00)00129-0 · Cited by 18,139
Quantitative assessment of tactile allodynia in the rat paw
Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M., & Yaksh, T. L. (1994) · Journal of Neuroscience Methods · doi:10.1016/0165-0270(94)90144-9 · Cited by 7,697
A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man
Bennett, G. J., & Xie, Y.-K. (1988) · Pain · doi:10.1016/0304-3959(88)90209-6 · Cited by 5,376
BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain
Coull, J. A. M., Beggs, S., Boudreau, D., Boivin, D., Tsuda, M., Inoue, K., Gravel, C., Salter, M. W., & De Koninck, Y. (2005) · Nature · doi:10.1038/nature04223 · Cited by 1,965
Self-citationThe Phasor Approach to Fluorescence Lifetime Imaging Analysis
Digman, M. A., Caiolfa, V. R., Zamai, M., & Gratton, E. (2008) · Biophysical Journal · doi:10.1529/biophysj.107.120154 · Cited by 1,145
Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain
Coull, J. A. M., Boudreau, D., Bachand, K., Prescott, S. A., Nault, F., Sík, A., Koninck, P. D., & Koninck, Y. D. (2003) · Nature · doi:10.1038/nature01868 · Cited by 1,118
Self-citationPerturbed Chloride Homeostasis and GABAergic Signaling in Human Temporal Lobe Epilepsy
Huberfeld, G., Wittner, L., Clemenceau, S., Baulac, M., Kaila, K., Miles, R., & Rivera, C. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.2761-07.2007 · Cited by 634
Boulenguez, P., Liabeuf, S., Bos, R., Bras, H., Jean-Xavier, C., Brocard, C., Stil, A., Darbon, P., Cattaert, D., Delpire, E., et al. (2010) · Nature Medicine · doi:10.1038/nm.2107 · Cited by 617
Rivera, C., Li, H., Thomas-Crusells, J., Lahtinen, H., Viitanen, T., Nanobashvili, A., Kokaia, Z., Airaksinen, M. S., Voipio, J., Kaila, K., et al. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200209011 · Cited by 566
Mechanism of Activity-Dependent Downregulation of the Neuron-Specific K-Cl Cotransporter KCC2
Rivera, C., Voipio, J., Thomas-Crusells, J., Li, H., Emri, Z., Sipilä, S., Payne, J. A., Minichiello, L., Saarma, M., & Kaila, K. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.5265-03.2004 · Cited by 515
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
Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations
Chen, B., Li, Y., Yu, B., Zhang, Z., Brommer, B., Williams, P. R., Liu, Y., Hegarty, S. V., Zhou, S., Zhu, J., et al. (2018) · Cell · doi:10.1016/j.cell.2018.06.005 · Cited by 253
Neurobiological bases of autism–epilepsy comorbidity: a focus on excitation/inhibition imbalance
Bozzi, Y., Provenzano, G., & Casarosa, S. (2018) · European Journal of Neuroscience · doi:10.1111/ejn.13595 · Cited by 250
Normal and abnormal coding of somatosensory stimuli causing pain
Prescott, S. A., Ma, Q., & De Koninck, Y. (2014) · Nature Neuroscience · doi:10.1038/nn.3629 · Cited by 210
Deidda, G., Bozarth, I. F., & Cancedda, L. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00119 · Cited by 192
Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse
Korpi, E. R., den Hollander, B., Farooq, U., Vashchinkina, E., Rajkumar, R., Nutt, D. J., Hyytiä, P., & Dawe, G. S. (2015) · Pharmacological Reviews · doi:10.1124/pr.115.010967 · Cited by 148
Allostatic mechanisms of opioid tolerance beyond desensitization and downregulation
Cahill, C. M., Walwyn, W., Taylor, A. M. W., Pradhan, A. A. A., & Evans, C. J. (2016) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.08.002 · Cited by 122
Is birth a critical period in the pathogenesis of autism spectrum disorders?
Ben-Ari, Y. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3956 · Cited by 117
Zhang, B., Yan, W., Zhu, Y., Yang, W., Le, W., Chen, B., Zhu, R., & Cheng, L. (2018) · Advanced Materials · doi:10.1002/adma.201705694 · Cited by 113
Taylor, A. M. W., Castonguay, A., Ghogha, A., Vayssiere, P., Pradhan, A. A. A., Xue, L., Mehrabani, S., Wu, J., Levitt, P., Olmstead, M. C., et al. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.221 · Cited by 109
Self-citationBoakye, P. A., Tang, S.-J., & Smith, P. A. (2021) · Frontiers in Pain Research · doi:10.3389/fpain.2021.698157 · Cited by 102
Thomas, A. M., Ostroumov, A., Kimmey, B. A., Taormina, M. B., Holden, W. M., Kim, K., Brown-Mangum, T., & Dani, J. A. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.030 · Cited by 50
Capsoni, S., Arisi, I., Malerba, F., D’Onofrio, M., Cattaneo, A., & Cherubini, E. (2022) · Brain Sciences · doi:10.3390/brainsci12060783 · Cited by 18
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
Data sources
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.
