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The α6 subunit-containing GABAA receptor: A novel drug target for inhibition of trigeminal activation

Fan PC 1 , Lai TH 2 , Hor CC 3 , Lee MT 4 , Huang P 5 , Sieghart W 6 Show all authors , Ernst M 6 , Knutson DE 7 , Cook J 7 , Chiou LC 8

Affiliations 

  • 1 Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan; Department of Pediatrics, National Taiwan University Hospital, Taipei, 10002, Taiwan; Clinical Center for Neuroscience and Behavioral, National Taiwan University Hospital, Taipei, 10002, Taiwan
  • 2 Department of Pediatrics, National Taiwan University Hospital, Taipei, 10002, Taiwan
  • 3 Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan
  • 4 Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan; Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia
  • 5 Department of Pediatrics, E-da Dachang Hospital, Kaohsiung, 807, Taiwan
  • 6 Center for Brain Research, Department of Molecular Neurosciences, Medical University Vienna, Vienna, 1090, Wien, Austria
  • 7 Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, WI, 53211, USA
  • 8 Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan; Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan; Clinical Center for Neuroscience and Behavioral, National Taiwan University Hospital, Taipei, 10002, Taiwan; Graduate Institute of Acupuncture Sciences, China Medical University, Taichung, 404, Taiwan. Electronic address: [email protected]
Neuropharmacology, 2018 09 15;140:1-13.
PMID: 30016665 DOI: 10.1016/j.neuropharm.2018.07.017

Abstract

Novel treatments against migraine are an urgent medical requirement. The α6 subunit-containing GABAA receptors (α6GABAARs) are expressed in trigeminal ganglia (TG), the hub of the trigeminal vascular system (TGVS) that is involved in the pathogenesis of migraine. Here we reveal an unprecedented role of α6GABAARs in ameliorating TGVS activation using several pharmacological approaches in an animal model mimicking pathological changes in migraine. TGVS activation was induced by intra-cisternal (i.c.) instillation of capsaicin in Wistar rats. Centrally, i.c. capsaicin activated the trigeminal cervical complex (TCC) measured by the increased number of c-Fos-immunoreactive (c-Fos-ir) TCC neurons. Peripherally, it elevated calcitonin gene-related peptide immunoreactivity (CGRP-ir) in TG and depleted CGRP-ir in the dura mater. Pharmacological approaches included a recently identified α6GABAAR-selective positive allosteric modulator (PAM), the pyrazoloquinolinone Compound 6, two α6GABAAR-active PAMs (Ro15-4513 and loreclezole), an α6GABAAR-inactive benzodiazepine (diazepam), an α6GABAAR-selective antagonist (furosemide), and a clinically effective antimigraine agent (topiramate). We examined effects of these compounds on both central and peripheral TGVS responses induced by i.c. capsaicin. Compound 6 (3-10 mg/kg, i.p.) significantly attenuated the TCC neuronal activation and TG CGRP-ir elevation, and dural CGRP depletion induced by capsaicin. All these effects of Compound 6 were mimicked by topiramate, Ro15-4513 and loreclezole, but not by diazepam. The brain-impermeable furosemide antagonized the peripheral, but not central, effects of Compound 6. These results suggest that the α6GABAAR in TG is a novel drug target for TGVS activation and that α6GABAAR-selective PAMs have the potential to be developed as a novel pharmacotherapy for migraine.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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