The α6 subunit-containing GABAA receptor: A novel drug target for inhibition of trigeminal activation
| Autor: | Pi-Chuan Fan, Pokai Huang, Lih-Chu Chiou, Chia Chun Hor, Daniel E. Knutson, Werner Sieghart, Tzu-Hsuan Lai, James M. Cook, Ming Tatt Lee, Margot Ernst |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Azides Allosteric modulator medicine.drug_class Calcitonin Gene-Related Peptide Loreclezole Quinolones Pharmacology Calcitonin gene-related peptide Article Benzodiazepines 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Furosemide Topiramate medicine Animals GABA-A Receptor Agonists GABA-A Receptor Antagonists Pyrazolones Receptor Benzodiazepine Diazepam Dose-Response Relationship Drug Chemistry GABAA receptor Antagonist Triazoles Receptors GABA-A Rats Infusions Intraventricular 030104 developmental biology Trigeminal Ganglion Capsaicin Dura Mater 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Neuropharmacology. 140:1-13 |
| ISSN: | 0028-3908 |
| Popis: | Novel treatments against migraine are an urgent medical requirement. α6 subunit-containing GABA(A) receptors (α6GABA(A)Rs) 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 α6GABA(A)Rs 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 α6GABA(A)R-selective positive allosteric modulator (PAM), the pyrazoloquinolinone Compound 6, two α6GABA(A)R-active PAMs (Ro15–4513 and loreclezole), an α6GABA(A)R-inactive benzodiazepine (diazepam), an α6GABA(A)R-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 α6GABA(A)R in TG is a novel drug target for TGVS activation and that α6GABA(A)R-selective PAMs have the potential to be developed as a novel pharmacotherapy for migraine. |
| Databáze: | OpenAIRE |
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