Matches in SemOpenAlex for { <https://semopenalex.org/work/W2131268267> ?p ?o ?g. }
Showing items 1 to 86 of
86
with 100 items per page.
- W2131268267 endingPage "212ec192" @default.
- W2131268267 startingPage "212ec192" @default.
- W2131268267 abstract "Looks can be deceiving. Take, for example, the nervous system disorders epilepsy, motor spasticity, and chronic neuropathic pain; their symptoms differ dramatically, but the underlying mechanisms of all three may converge on an underfunctioning K+ Cl– cotransporter (KCC2), suggesting that KCC2 could be a therapeutic target for these disorders. Now, Gagnon et al . report on a high-throughput screen for drugs that enhance the activity of KCC2. Binding of the neurotransmitters γ-aminobutyric acid (GABA) and glycine to GABAA and glycine receptors, respectively, on postsynaptic neurons typically results in a flux of chloride ions (Cl–) into the cell, membrane hyperpolarization, and neuronal inhibition. The Cl– influx is driven by a concentration gradient across the cell membrane, with lower amounts of Cl– being present inside versus outside of the cell. KCC2 maintains the gradient by pumping Cl– out of the cell. When KCC2 activity is lower than normal, central nervous system disorders arise. The authors engineered a cell culture assay for high-throughput fluorescent quantitation of Cl– efflux via KCC2. After assaying a library of 92,500 compounds, the authors identified 78 positive hits that reduced intracellular Cl– concentrations. One of the hits, CL-058, was selected on the basis of its lack of cytotoxic effects, ease of synthesis, and drug-like properties. More than 300 related molecules were then synthesized, and one of these analogs, CLP257, selectively restored impaired Cl– transport in neurons (in adult rat spinal cord slices) with reduced KCC2 activity. Furthermore, the authors demonstrated that the Cl– extrusion effect by CLP257 alleviated hypersensitivity to neuropathic pain in an animal model. Compared with pregabalin, which is commonly used to treat neuropathic pain in humans, CLP257 was not only equally effective in reducing the pain in the animal model, it also displayed fewer motor side effects.The new findings are encouraging for three main reasons. First, oral administration of a small molecule was able to enhance KCC2 activity; second, KCC2 can serve as a therapeutic target for effective reduction of neuropathic pain with minor motor side effects; and third, exploration of KCC2 as a treatable target for other neurological disorders may now be feasible. M. Gagnon et al ., Chloride extrusion enhancers as novel therapeutics for neurological diseases. Nat. Med . 19 , 1524–1528 (2013). [[Full Text]][1] [1]: http://www.nature.com/nm/journal/v19/n11/abs/nm.3356.html" @default.
- W2131268267 created "2016-06-24" @default.
- W2131268267 creator A5040304278 @default.
- W2131268267 date "2013-11-20" @default.
- W2131268267 modified "2023-09-27" @default.
- W2131268267 title "Removing Salt from the Wound" @default.
- W2131268267 doi "https://doi.org/10.1126/scitranslmed.3007983" @default.
- W2131268267 hasPublicationYear "2013" @default.
- W2131268267 type Work @default.
- W2131268267 sameAs 2131268267 @default.
- W2131268267 citedByCount "0" @default.
- W2131268267 crossrefType "journal-article" @default.
- W2131268267 hasAuthorship W2131268267A5040304278 @default.
- W2131268267 hasConcept C104317684 @default.
- W2131268267 hasConcept C12554922 @default.
- W2131268267 hasConcept C131453863 @default.
- W2131268267 hasConcept C149011108 @default.
- W2131268267 hasConcept C1491633281 @default.
- W2131268267 hasConcept C168258287 @default.
- W2131268267 hasConcept C169760540 @default.
- W2131268267 hasConcept C170493617 @default.
- W2131268267 hasConcept C17077164 @default.
- W2131268267 hasConcept C178790620 @default.
- W2131268267 hasConcept C185592680 @default.
- W2131268267 hasConcept C188053792 @default.
- W2131268267 hasConcept C197341189 @default.
- W2131268267 hasConcept C537181965 @default.
- W2131268267 hasConcept C55493867 @default.
- W2131268267 hasConcept C66974803 @default.
- W2131268267 hasConcept C71240020 @default.
- W2131268267 hasConcept C79879829 @default.
- W2131268267 hasConcept C86803240 @default.
- W2131268267 hasConcept C95444343 @default.
- W2131268267 hasConcept C98274493 @default.
- W2131268267 hasConceptScore W2131268267C104317684 @default.
- W2131268267 hasConceptScore W2131268267C12554922 @default.
- W2131268267 hasConceptScore W2131268267C131453863 @default.
- W2131268267 hasConceptScore W2131268267C149011108 @default.
- W2131268267 hasConceptScore W2131268267C1491633281 @default.
- W2131268267 hasConceptScore W2131268267C168258287 @default.
- W2131268267 hasConceptScore W2131268267C169760540 @default.
- W2131268267 hasConceptScore W2131268267C170493617 @default.
- W2131268267 hasConceptScore W2131268267C17077164 @default.
- W2131268267 hasConceptScore W2131268267C178790620 @default.
- W2131268267 hasConceptScore W2131268267C185592680 @default.
- W2131268267 hasConceptScore W2131268267C188053792 @default.
- W2131268267 hasConceptScore W2131268267C197341189 @default.
- W2131268267 hasConceptScore W2131268267C537181965 @default.
- W2131268267 hasConceptScore W2131268267C55493867 @default.
- W2131268267 hasConceptScore W2131268267C66974803 @default.
- W2131268267 hasConceptScore W2131268267C71240020 @default.
- W2131268267 hasConceptScore W2131268267C79879829 @default.
- W2131268267 hasConceptScore W2131268267C86803240 @default.
- W2131268267 hasConceptScore W2131268267C95444343 @default.
- W2131268267 hasConceptScore W2131268267C98274493 @default.
- W2131268267 hasIssue "212" @default.
- W2131268267 hasLocation W21312682671 @default.
- W2131268267 hasOpenAccess W2131268267 @default.
- W2131268267 hasPrimaryLocation W21312682671 @default.
- W2131268267 hasRelatedWork W135045138 @default.
- W2131268267 hasRelatedWork W1578110071 @default.
- W2131268267 hasRelatedWork W1586957003 @default.
- W2131268267 hasRelatedWork W1615851555 @default.
- W2131268267 hasRelatedWork W184725565 @default.
- W2131268267 hasRelatedWork W1971354794 @default.
- W2131268267 hasRelatedWork W1995116158 @default.
- W2131268267 hasRelatedWork W2005755710 @default.
- W2131268267 hasRelatedWork W2016122143 @default.
- W2131268267 hasRelatedWork W2020255634 @default.
- W2131268267 hasRelatedWork W2059067548 @default.
- W2131268267 hasRelatedWork W2070360463 @default.
- W2131268267 hasRelatedWork W2125414446 @default.
- W2131268267 hasRelatedWork W2145861425 @default.
- W2131268267 hasRelatedWork W2145998855 @default.
- W2131268267 hasRelatedWork W2152828053 @default.
- W2131268267 hasRelatedWork W2335883470 @default.
- W2131268267 hasRelatedWork W2906523287 @default.
- W2131268267 hasRelatedWork W3025616718 @default.
- W2131268267 hasRelatedWork W3037760323 @default.
- W2131268267 hasVolume "5" @default.
- W2131268267 isParatext "false" @default.
- W2131268267 isRetracted "false" @default.
- W2131268267 magId "2131268267" @default.
- W2131268267 workType "article" @default.