癫痫持续状态
苯二氮卓
变构调节
运动前神经元活动
医学
化学
γ-氨基丁酸受体
药理学
神经科学
抗惊厥药
癫痫
心理学
生物化学
受体
作者
Rebecca M. Jarvis,Shu Fun Josephine Ng,Anna J. Nathanson,Ross A. Cardarelli,Krithika Abiraman,Fergus Wade,Aidan Evans‐Strong,Marina P. Fernandez-Campa,Tarek Z. Deeb,Joshua L. Smalley,Tanguy Jamier,Ian Gurrell,Lisa McWilliams,Aarti Kawatkar,Leslie Conway,Qi Wang,Roland W. Bürli,Nicholas J. Brandon,Iain P. Chessell,Aaron Goldman,Jamie Maguire,Stephen J. Moss
标识
DOI:10.1016/j.xcrm.2023.100957
摘要
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.
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