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

Abstract

Novel treatments against migraine are an urgent medical requirement. The α6 subunit-containing GABA receptors (α6GABARs) 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 α6GABARs 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 α6GABAR-selective positive allosteric modulator (PAM), the pyrazoloquinolinone Compound 6, two α6GABAR-active PAMs (Ro15-4513 and loreclezole), an α6GABAR-inactive benzodiazepine (diazepam), an α6GABAR-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 α6GABAR in TG is a novel drug target for TGVS activation and that α6GABAR-selective PAMs have the potential to be developed as a novel pharmacotherapy for migraine.

Plasma Calcitonin Gene-Related Peptide: A Potential Biomarker for Diagnosis and Therapeutic Responses in Pediatric Migraine

“…Pre-clinical studies in migraine animal models have shown that topiramate inhibited neurogenic dural vasodilation by inhibiting CGRP release from pre-junctional trigeminal neurons induced by noxious inoculation (17, 51). We also found that topiramate inhibited CGRP immunoreactivity in the trigeminal ganglia and dura (23, 24) of rats in a capsaicin-stimulated migraine model (22). Topiramate has been also reported to enhance GABA currents of GABA A receptors, including the α6 subunit-containing GABA A receptors (α6GABA A Rs) (52).…”

“…Topiramate has been also reported to enhance GABA currents of GABA A receptors, including the α6 subunit-containing GABA A receptors (α6GABA A Rs) (52). The α6GABA A Rs are highly expressed in trigeminal ganglia (23, 53) and were recently identified to be a novel drug target for migraine treatment (23). It remains to be elucidated whether the α6GABA A R-modulating effect of topiramate contributes to its antimigraine activity.…”

Two Distinct Populations of α1α6-Containing GABAA-Receptors in Rat Cerebellum

“…In the current study, we mostly focused on receptors containing the α6-subunit, which have gained recent attention as potential novel future drug targets. α6-containing GABAA receptors have been reported to contribute to the alleviation of sensorimotor gating deficits (Chiou et al, 2018 ) and orofacial pain and migraine (Fan et al, 2018 ) in animal and cell models. Moreover, models of essential tremor and trigeminal neuropathic pain also have been demonstrated to benefit from drugs that act on α6-containing GABAA receptors (Handforth et al, 2018 ; Vasović et al, 2019 ).…”

“…It was suggested that α6 subunits are recruited for the strengthening of synapses and added to α1 subunit containing postsynaptic densities (Accardi et al, 2015 ). Recent research has identified a number of putative pathophysiological roles which involve α6-containing receptors, and targeting these is considered an interesting strategy for disorders with sensorimotor gating deficits (Chiou et al, 2018 ), essential tremor (Handforth et al, 2018 ), and by way of receptors thought to be localized in the trigeminal ganglia, trigeminal neuropathic pain states (Puri et al, 2012 ; Vasović et al, 2019 ) and migraine (Fan et al, 2018 ).…”

Age-Dependent Anti-migraine Effects of Valproic Acid and Topiramate in Rats

“…This peptide was found in ranging from approximately 35% to almost 50% neurons of the TG in rats and man, present in small-sized cells previously ( Lazarov, 2002 ). In capsaicin-treated rats, we found CGRP was densely distributed in TG neurons ( Fan et al, 2018 ). In contrast to the inhibition of TNC neuronal activation via GABA A receptors, whether VPA treats migraine is mediated by CGRP remains unclear.…”