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

Cell Rep Med. 2023 Mar 21;4(3):100957. doi: 10.1016/j.xcrm.2023.100957. Epub 2023 Mar 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzodiazepines / pharmacology
  • Benzodiazepines / therapeutic use
  • Mice
  • Seizures / metabolism
  • Status Epilepticus* / drug therapy
  • Symporters* / metabolism
  • gamma-Aminobutyric Acid / metabolism


  • Benzodiazepines
  • gamma-Aminobutyric Acid
  • Symporters