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

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

  • Cell Rep Med. 2023 Mar 2;100957. doi: 10.1016/j.xcrm.2023.100957.
Rebecca Jarvis 1,  Shu Fun Josephine Ng 2,  Anna J Nathanson 2,  Ross A Cardarelli 2,  Krithika Abiraman 2,  Fergus Wade 2,  Aidan Evans-Strong 2,  Marina P Fernandez-Campa 2,  Tarek Z Deeb 2,  Joshua L Smalley 2,  Tanguy Jamier 1,  Ian K Gurrell 1,  Lisa McWilliams 3,  Aarti Kawatkar 4,  Leslie C Conway 2,  Qi Wang 5,  Roland W Burli 1,  Nicholas J Brandon 5,  Iain P Chessell 1,  Aaron J Goldman 6,  Jamie L Maguire 2,  Stephen J Moss 7
Affiliations

Affiliations

  • 1 Discovery, Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
  • 2 Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
  • 3 Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK.
  • 4 Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Boston, MA, USA.
  • 5 Discovery, Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Boston, MA, USA.
  • 6 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 7 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.
PMID: 36889319 DOI: 10.1016/j.xcrm.2023.100957
Abstract

Hyperpolarizing GABAAR 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 GABAAR-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.

Keywords

EEG; KCC2; benzodiazepine; epilepsy; neuronal Cl(−) extrusion; neuronal death; neuroprotection; refractory status epilepticus; synaptic inhibition.

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