English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Alpha-5 gamma-aminobutyric acid type A receptors (α5-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 α5-GABAAR in mice with ischemic stroke improved recovery of function by normalizing exaggerated perilesional α5-GABAAR-dependent tonic inhibition. S44819 is a novel competitive selective antagonist of the α5-GABAAR at the GABA-binding site. Pharmacological modulation of α5-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 α5-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.

Effects of the Selective α5-GABAAR Antagonist S44819 on Excitability in the Human Brain: A TMS–EMG and TMS–EEG Phase I Study