The α6 subunit-containing GABAA receptor: A novel drug target for inhibition of trigeminal activation. (15th September 2018)

• Record Type: Journal Article
• Authors: Fan, Pi-Chuan; Lai, Tzu-Hsuan; Hor, Chia Chun; Lee, Ming Tatt; Huang, Pokai; Sieghart, Werner; Ernst, Margot; Knutson, Daniel E.; Cook, James; Chiou, Lih-Chu
• Is Part Of: Neuropharmacology. Volume 140(2018)
• Page Start: 1
• Page End: 13
• Publication Date: 2018-09-15
• Subjects: Trigeminovascular activation -- α6GABAAR -- Positive allosteric modulator -- Trigeminal ganglia -- Calcitonin gene-related peptide; α6GABAAR α6 subunit-containing GABAA receptor -- aCSF artificial cerebrospinal fluid -- BBB blood-brain barrier -- c-Fos-ir c-Fos-immunoreactive -- CGRP-ir calcitonin gene-related peptide immunoreactivity -- GABAAR GABAA receptor -- i.c. intra-cisternal injection -- PAM positive allosteric modulator -- TCC trigeminal cervical complex -- TG trigeminal ganglia -- TGVS trigeminal vascular system -- TMJ temporomandibular joint -- TNC trigeminal nucleus caudalis -- TRPV1 transient receptor potential vanilloid type-1 channel; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.07.017
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Novel treatments against migraine are an urgent medical requirement. The α6 subunit-containing GABAA receptors (α6GABAA 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 α6GABAA 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 α6GABAA R-selective positive allosteric modulator (PAM), the pyrazoloquinolinone Compound 6, two α6GABAA R-active PAMs (Ro15-4513 and loreclezole), an α6GABAA R-inactive benzodiazepine (diazepam), an α6GABAA 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 α6GABAA R in TG is a novel drug target for TGVS activation and that α6GABAA R-selective PAMs have the potential to be developed as a novel pharmacotherapy for migraine. Highlights: α6GABAA R positive modulators inhibited central and peripheral trigeminal responses in a migraine model. Diazepam, an α6GABAA R-inactive ligand, had no effect in this migraine model. Systemic furosemide, an α6GABAA R blocker, inhibited peripheral responses only. The α6GABAA R in trigeminal ganglia is a novel target for migraine treatment. α6GABAA R positive allosteric modulators represent a potential treatment option for migraine.