Global transgenic upregulation of KCC2 confers enhanced diazepam efficacy in treating sustained seizures
Global transgenic upregulation of KCC2 confers enhanced diazepam efficacy in treating sustained seizures
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DOI：
10.1111/epi.17097
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发表时间：
2021-11-17
期刊：
影响因子：
5.6
通讯作者：
Moorhouse, Andrew J.
中科院分区：
文献类型：
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作者：
Cheung, Dennis L.;Cooke, Matthew J.;Moorhouse, Andrew J.
苯二氮卓类药物抗惊厥疗效降低是癫痫持续状态治疗中的一个问题，高达50%的患者首次给药无效。KCC 2是一种神经元K+-Cl-共转运蛋白，有助于设定和维持细胞内Cl-浓度。KCC 2功能下调是苯二氮卓类耐药的潜在因素。我们使用雄性和雌性多西环素诱导的条件转基因小鼠来测试这一想法，以增加锥体神经元中KCC 2的功能表达。我们给小鼠施用两个剂量的化学惊厥剂红藻氨酸（5 mg/kg，i. p.）间隔60分钟，用脑电图（EEG）记录量化所产生的癫痫发作。KCC 2在化学惊厥药激发前的过表达并不影响癫痫发作潜伏期或其他癫痫发作严重程度的测量，但它确实增加了地西泮阻止EEG癫痫发作的疗效。与对照小鼠相比，KCC 2过表达小鼠的尖峰频率、癫痫发作时间和地西泮（5 mg/kg，i.p）后的EEG频谱功率均显著降低。我们的研究结果表明，在持续癫痫发作期间苯二氮卓类药物抵抗的背景下，单独解决受损的Cl-稳态可明显提高γ-氨基丁酸（GABA）能抑制的疗效。因此，我们建议同时靶向KCC 2和GABA（A）受体作为改善当前抗惊厥治疗策略的途径。
Reduced anticonvulsant efficacy of benzodiazepines is a problem in the treatment of status epilepticus, with up to 50% of patients failing to respond to their first dose. KCC2 is a neuronal K+-Cl- co-transporter that helps set and maintain intracellular Cl- concentrations. KCC2 functional downregulation is a potential contributor to benzodiazepine resistance. We tested this idea using male and female doxycycline-inducible, conditional transgenic mice to increase the functional expression of KCC2 in pyramidal neurons. We administered mice with two doses of the chemoconvulsant kainic acid (5 mg/kg, i.p.) 60 min apart and quantified the resultant seizures with electroencephalography (EEG) recordings. Overexpression of KCC2 prior to the chemoconvulsant challenge did not affect seizure latency or other measures of seizure severity, but it did increase diazepam's efficacy in stopping EEG seizures. Spike rate, time in seizure, and EEG spectral power following diazepam (5 mg/kg, i.p) were all significantly lower in KCC2 overexpression mice as compared to control mice. Our results indicate that, in the context of benzodiazepine resistance during sustained seizures, addressing impaired Cl- homeostasis alone appreciably improves the efficacy of gamma-aminobutyric acid (GABA)ergic inhibition. We therefore suggest the simultaneous targeting of KCC2 and GABA(A) receptors as a pathway for improving current anticonvulsant therapeutic strategies.