Direct activation of KCC2 arrests benzodiazepine refractory status epilepticus and limits the subsequent neuronal injury in mice.

Autor: Jarvis R; Discovery, Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Josephine Ng SF; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA., Nathanson AJ; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA., Cardarelli RA; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA., Abiraman K; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA., Wade F; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA., Evans-Strong A; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA., Fernandez-Campa MP; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA., Deeb TZ; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA., Smalley JL; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA., Jamier T; Discovery, Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Gurrell IK; Discovery, Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., McWilliams L; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK., Kawatkar A; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Boston, MA, USA., Conway LC; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA., Wang Q; Discovery, Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Boston, MA, USA., Burli RW; Discovery, Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Brandon NJ; Discovery, Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Boston, MA, USA., Chessell IP; Discovery, Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Goldman AJ; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA., Maguire JL; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA., Moss SJ; Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA; Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1 6BT, UK. Electronic address: stephen.moss@tufts.edu.
Jazyk: angličtina
Zdroj: Cell reports. Medicine [Cell Rep Med] 2023 Mar 21; Vol. 4 (3), pp. 100957. Date of Electronic Publication: 2023 Mar 07.
DOI: 10.1016/j.xcrm.2023.100957
Abstrakt: Hyperpolarizing GABA A R currents, the unitary events that underlie synaptic inhibition, are dependent upon efficient Cl - extrusion, a process that is facilitated by the neuronal specific K + /Cl - co-transporter KCC2. Its activity is also a determinant of the anticonvulsant efficacy of the canonical GABA A R-positive allosteric: benzodiazepines (BDZs). Compromised KCC2 activity is implicated in the pathophysiology of status epilepticus (SE), a medical emergency that rapidly becomes refractory to BDZ (BDZ-RSE). Here, we have identified small molecules that directly bind to and activate KCC2, which leads to reduced neuronal Cl - accumulation and excitability. KCC2 activation does not induce any overt effects on behavior but prevents the development of and terminates ongoing BDZ-RSE. In addition, KCC2 activation reduces neuronal cell death following BDZ-RSE. Collectively, these findings demonstrate that KCC2 activation is a promising strategy to terminate BDZ-resistant seizures and limit the associated neuronal injury.
Competing Interests: Declaration of interests S.J.M. serves as a consultant for AstraZeneca, Ovid Therapeutics, and SAGE Therapeutics, relationships that are regulated by Tufts University. S.J.M. holds equity in SAGE Therapeutics and Ovid Therapeutics. R.J., T.J., I.K.G., A.K., L.M., and I.P.C. are employees of AstraZeneca and hold equity. A.G. is an employee of Ovid Therapeutics and holds equity. R.J. and R.W.B. hold a patent describing the KCC2 activators, WO2021180952A1 (https://worldwide.espacenet.com).
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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