Targeting ischemia-induced KCC2 hypofunction rescues refractory neonatal seizures and mitigates epileptogenesis in a mouse model.
Targeting ischemia-induced KCC2 hypofunction rescues refractory neonatal seizures and mitigates epileptogenesis in a mouse model.
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靶向缺血诱导的KCC2功能减退在小鼠模型中挽救难治性新生儿癫痫发作并减轻癫痫发生
DOI：
10.1126/scisignal.abg2648
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发表时间：
2021-11-09
影响因子：
7.3
通讯作者：
Kadam SD
中科院分区：
文献类型：
--
作者：
Sullivan BJ;Kipnis PA;Carter BM;Shao LR;Kadam SD
新生儿癫痫发作对早期发现、急性治疗和长期合并症提出了临床挑战。它们通常由缺氧缺血性脑病引起，并且一线抗癫痫药物苯巴比妥通常难以治疗。一种提出的新生儿癫痫发作期间苯巴比妥无效的机制是神经元特异性 K+/Cl− 协同转运蛋白 2 (KCC2) 的丰度和功能降低，该蛋白在出生后发育过程中维持氯稳态并促进 GABA 磷酸化抑制。在这里，我们研究了这种机制是否具有因果关系以及是否可以通过 KCC2 功能增强来挽救。在难治性缺血性新生儿癫痫发作的 CD-1 小鼠模型中，用 KCC2 功能增强剂 CLP290 治疗可挽救苯巴比妥疗效，增加 KCC2 丰度，并防止癫痫发生（通过视频脑电图监测进行量化）。这些效应可通过 KCC2 非磷酸化突变体（S940A 或 T906A 和 T1007A）的敲入表达来阻止，表明 KCC2 磷酸化可调节新生儿癫痫易感性和 CLP290 介导的 KCC2 功能增强。因此，我们的研究结果验证了 KCC2 作为难治性新生儿癫痫发作的临床相关靶点，并为未来的药物开发提供了见解。
Neonatal seizures pose a clinical challenge in their early detection, acute management, and long-term comorbidities. They are often caused by hypoxic-ischemic encephalopathy and are frequently refractory to the first-line anti-seizure medication phenobarbital. One proposed mechanism for phenobarbital inefficacy during neonatal seizures is the reduced abundance and function of the neuron-specific K+/Cl− cotransporter 2 (KCC2), which maintains chloride homeostasis and promotes GABAergic inhibition upon its phosphorylation during postnatal development. Here, we investigated whether this mechanism is causal and whether it can be rescued by KCC2 functional enhancement. In a CD-1 mouse model of refractory ischemic neonatal seizures, treatment with the KCC2 functional enhancer CLP290 rescued phenobarbital efficacy, increased KCC2 abundance, and prevented the development of epileptogenesis, as quantified by video electroencephalogram monitoring. These effects were prevented by knock-in expression of nonphosphorylatable mutants of KCC2 (S940A or T906A and T1007A), indicating that KCC2 phosphorylation regulates both neonatal seizure susceptibility and CLP290-mediated KCC2 functional enhancement. Our findings therefore validate KCC2 as a clinically relevant target for refractory neonatal seizures and provide insights for future drug development.
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影响因子：
82.9
作者：
通讯作者：
--
影响因子：
64.5
作者：
Chen B;Li Y;Yu B;Zhang Z;Brommer B;Williams PR;Liu Y;Hegarty SV;Zhou S;Zhu J;Guo H;Lu Y;Zhang Y;Gu X;He Z
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He Z
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16.2
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Hübner, CA;Stein, V;Jentsch, TJ
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Jentsch, TJ
影响因子：
5.6
作者：
Johne, Marie;Roemermann, Kerstin;Loescher, Wolfgang
通讯作者：
Loescher, Wolfgang
影响因子：
5.6
作者：
Glass, Hannah C.;Soul, Janet S.;Shellhaas, Renee A.
通讯作者：
Shellhaas, Renee A.