Direct activation of KCC2 arrests benzodiazepine refractory status epilepticus and limits the subsequent neuronal injury in mice.
Cell Rep Med
; 4(3): 100957, 2023 03 21.
Article
in En
| MEDLINE
| ID: mdl-36889319
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Status Epilepticus
/
Symporters
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Cell Rep Med
Year:
2023
Document type:
Article
Affiliation country:
Reino Unido