Jarvis, R;
Josephine Ng, SF;
Nathanson, AJ;
Cardarelli, RA;
Abiraman, K;
Wade, F;
Evans-Strong, A;
... Moss, SJ; + view all
(2023)
Direct activation of KCC2 arrests benzodiazepine refractory status epilepticus and limits the subsequent neuronal injury in mice.
Cell Reports Medicine
, 4
(3)
, Article 100957. 10.1016/j.xcrm.2023.100957.
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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.
| Type: | Article |
|---|---|
| Title: | Direct activation of KCC2 arrests benzodiazepine refractory status epilepticus and limits the subsequent neuronal injury in mice |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.xcrm.2023.100957 |
| Publisher version: | https://doi.org/10.1016/j.xcrm.2023.100957 |
| Language: | English |
| Additional information: | © 2023 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
| Keywords: | EEG, KCC2, benzodiazepine, epilepsy, neuronal Cl(−) extrusion, neuronal death, neuroprotection, refractory status epilepticus, synaptic inhibition |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10167698 |
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