AUTHOR=Fan Pi-Chuan , Chiou Lih-Chu , Lai Tzu-Hsuan , Sharmin Dishary , Cook James , Lee Ming Tatt 

TITLE=The deuterated pyrazoloquinolinone targeting α6 subunit-containing GABAA receptor as novel candidate for inhibition of trigeminovascular system activation: implication for migraine therapy

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1451634

DOI=10.3389/fphar.2024.1451634

ISSN=1663-9812

ABSTRACT=<sec><title>Introduction</title><p>The α6 subunit-containing GABA<sub>A</sub> receptors (α6GABA<sub>A</sub>Rs) are highly expressed in the trigeminal ganglia (TG), the sensory hub of the trigeminovascular system (TGVS). Hypo-GABAergic transmission in the TG was reported to contribute to migraine-related behavioral and histopathological phenotypes. Previously, we found that Compound 6, an α6GABA<sub>A</sub>R-selective positive allosteric modulator (PAM), significantly alleviated TGVS activation-induced peripheral and central sensitization in a capsaicin-induced migraine-mimicking model.</p></sec><sec><title>Methods</title><p>Here, we tested whether the deuterated analogues of Compound 6, namely DK-1-56-1 and RV-I-29, known to have longer half-lives than the parent compound, can exert a similar therapeutic effect in the same model. The activation of TGVS was triggered by intra-cisternal (<italic>i.c.</italic>) instillation of capsaicin in male Wistar rats. Centrally, <italic>i.c.</italic> capsaicin increased the quantity of c-Fos-immunoreactive (c-Fos-ir) neurons in the trigeminal cervical complex (TCC). Peripherally, it increased the calcitonin gene-related peptide immunoreactivity (CGRP-ir) in TG, and caused CGRP release, leading to CGRP depletion in the dura mater.</p></sec><sec><title>Results</title><p>DK-I-56-1 and RV-I-29, administered intraperitoneally (<italic>i.p.</italic>), significantly ameliorated the TCC neuronal activation, TG CGRP-ir elevation, and dural CGRP depletion induced by capsaicin, with DK-I-56-1 demonstrating better efficacy. The therapeutic effects of 3 mg/kg DK-I-56-1 are comparable to that of 30 mg/kg topiramate. Notably, <italic>i.p.</italic> administered furosemide, a blood-brain-barrier impermeable α6GABA<sub>A</sub>R-selective antagonist, prevented the effects of DK-I-56-1 and RV-I-29. Lastly, orally administered DK-I-56-1 has a similar pharmacological effect.</p></sec><sec><title>Discussion</title><p>These results suggest that DK-I-56-1 is a promising candidate for novel migraine pharmacotherapy, through positively modulating TG α6GABA<sub>A</sub>Rs to inhibit TGVS activation, with relatively favourable pharmacokinetic properties.</p></sec>