Effects of the Selective α5-GABAAR Antagonist S44819 on Excitability in the Human Brain: A TMS-EMG and TMS-EEG Phase I Study
Effects of the Selective α5-GABAAR Antagonist S44819 on Excitability in the Human Brain: A TMS-EMG and TMS-EEG Phase I Study
复制标题
DOI：
10.1523/jneurosci.1689-16.2016
复制
发表时间：
2016-12-07
影响因子：
5.3
通讯作者：
Ziemann, Ulf
中科院分区：
文献类型：
--
作者：
Darmani, Ghazaleh;Zipser, Carl M.;Ziemann, Ulf
α-5-氨基丁酸型受体(α-5-GABAARs)位于突触外，通过紧张性抑制调节神经元的兴奋性，对可塑性和学习等过程起着至关重要的作用。例如，在缺血性中风小鼠中，对阿尔法5-GABAAR的药理阻断通过正常化被夸大的依赖于阿尔法5-GABAAR的紧张抑制来改善功能的恢复。S44819是一种新型的GABA结合部位的α5-GABAAR竞争性选择性拮抗剂。在人脑中，从未研究过α5-GABAAR介导的紧张性抑制的药理调节。在这里，我们使用经颅磁刺激(TMS)来测试单次口服50和100毫克S44819对18名健康年轻人皮层兴奋性的肌电(EMG)和脑电(EEG)测量的影响，这是一项随机、双盲、安慰剂对照、交叉的I期研究。100毫克而不是50毫克的S44819降低了主动运动阈值，产生0.5 mV运动诱发电位所需的强度，以及N45的幅度，N45是TMS诱发EEG反应的GABA能成分。S44819峰值血药浓度与N45波幅降低呈正相关。短间隔皮质内抑制，突触GABA能抑制的TMS-EMG测量，以及TMS诱发的EEG反应的其他成分仍未受到影响。这些发现首次提供了证据表明，特定的α5-GABAAR拮抗剂S44819到达人类大脑皮层，增加了大脑皮层的兴奋性。这些数据为S44819在人类临床试验中的进一步开发提供了依据，以测试其在促进缺血性中风后功能恢复方面的有效性。
Alpha-5 gamma-aminobutyric acid typeAreceptors (alpha 5-GABAARs) are located extrasynaptically, regulate neuronal excitability through tonic inhibition, and are fundamentally important for processes such as plasticity and learning. For example, pharmacological blockade of alpha 5-GABAAR in mice with ischemic stroke improved recovery of function by normalizing exaggerated perilesional alpha 5-GABAAR-dependent tonic inhibition. S44819 is a novel competitive selective antagonist of the alpha 5-GABAAR at the GABA-binding site. Pharmacological modulation of alpha 5-GABAAR-mediated tonic inhibition has never been investigated in the human brain. Here, we used transcranial magnetic stimulation (TMS) to test the effects of a single oral dose of 50 and 100 mg of S44819 on electromyographic (EMG) and electroencephalographic (EEG) measures of cortical excitability in 18 healthy young adults in a randomized, double-blinded, placebo-controlled, crossover phase I study. A dose of 100 mg, but not 50 mg, of S44819 decreased active motor threshold, the intensity needed to produce a motor evoked potential of 0.5 mV, and the amplitude of the N45, a GABAAergic component of the TMS-evoked EEG response. The peak serum concentration of 100 mg S44819 correlated directly with the decrease in N45 amplitude. Short-interval intracortical inhibition, a TMS-EMG measure of synaptic GABAAergic inhibition, and other components of the TMS-evoked EEG response remained unaffected. These findings provide first time evidence that the specific alpha 5-GABAAR antagonist S44819 reached human cortex to impose an increase in cortical excitability. These data warrant further development of S44819 in a human clinical trial to test its efficacy in enhancing recovery of function after ischemic stroke.