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
  • 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: [email protected].
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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