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

Neuropharmacology
Pi-Chuan FanLih-Chu Chiou

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 a...Continue Reading

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Citations

Oct 16, 2018·Frontiers in Pharmacology·Pokai HuangPi-Chuan Fan
Oct 29, 2020·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Hung-Ruei TzengLih-Chu Chiou
Oct 31, 2020·Frontiers in Synaptic Neuroscience·Petra ScholzeMargot Ernst
Jun 23, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Jelena R MitrovićSnežana D Savić

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