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

Hyperpolarizing GABA_AR 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_AR-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.