title: Effects of the Selective α5-GABAAR Antagonist S44819 on Excitability in the Human Brain: A TMS-EMG and TMS-EEG Phase I Study.
abstract: 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.
  
  
  
  The extrasynaptic α-5 gamma-aminobutyric acid type A receptor (α5-GABAAR) regulates neuronal excitability through tonic inhibition in the mammalian brain. Tonic inhibition is important for many fundamental processes such as plasticity and learning. Pharmacological modulation of α5-GABAAR-mediated tonic inhibition has never been investigated in the human brain. This study demonstrates that S44819, a selective α5-GABAAR antagonist, increases cortical excitability in healthy human subjects, as indicated by specific markers of transcranial magnetic stimulation-induced muscle and brain responses measured by electromyography and electroencephalography. Our findings imply that tonic inhibition in human cortex can be modified effectively and that this modification can be quantified with noninvasive brain stimulation methods. The actions of S44819 may be suitable to improve plasticity and learning.
authors.affiliation: Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Darmani
authors.affiliation: Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Carl M
authors.initials: CM
authors.lastname: Zipser
authors.affiliation: Department of Clinical Pharmacology, University Hospital Tübingen, 72076 Tübingen, Germany.
authors.forename: Gabriele M
authors.identifier: 0000-0001-6916-1636
authors.initials: GM
authors.lastname: Böhmer
authors.affiliation: Institut de Recherches Internationales Servier (IRIS), 92284 Suresnes, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Deschet
authors.affiliation: Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Müller-Dahlhaus
authors.affiliation: Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Paolo
authors.identifier: 0000-0002-9290-1804
authors.initials: P
authors.lastname: Belardinelli
authors.affiliation: Department of Clinical Pharmacology, University Hospital Tübingen, 72076 Tübingen, Germany.|Department of Pharmacy and Biochemistry, University of Tübingen, 72076 Tübingen, Germany, and.|Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany, ulf.ziemann@uni-tuebingen.de.
authors.forename: Ulf
authors.identifier: 0000-0001-8372-3615
authors.initials: U
authors.lastname: Ziemann
mesh_terms: D000328:Adult; D001921:Brain / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004569:Electroencephalography / Q000187:drug effects; D004576:Electromyography / Q000187:drug effects; D019054:Evoked Potentials, Motor / Q000187:drug effects; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D011963:Receptors, GABA-A / Q000187:drug effects*; D050781:Transcranial Magnetic Stimulation / Q000379:methods*; D055815:Young Adult
chemical_list: D058787:GABA-A Receptor Antagonists; C527986:GABRA5 protein, human; D011963:Receptors, GABA-A
keywords: TMS–EEG; excitability; human cortex; motor evoked potential; tonic inhibition; α5-GABAAR