Olcegepant

Migraine remains an unmet medical need, even with new calcitonin gene-related peptide (CGRP)-targeting treatments. The α6 subunit (Gabra6)-containing GABA_A receptors (α6GABA_ARs) are abundant in trigeminal ganglia (TG). We evaluated the possible anti-migraine efficacy and mechanism of DK-I-56-1, a druggable α6GABA_AR-selective positive allosteric modulator (PAM), using a chronic migraine model induced by repeated intermittent nitroglycerin (riNTG) injections (10 mg/kg, i.p., every 2 days for a total of 5 doses). Chronic and acute allodynic responses of riNTG-treated ICR mice of both sexes were assessed by reduced mechanical withdrawal thresholds in their periorbital areas, and their chronic cephalic pain by elevated grimace scores. riNTG induced long-lasting chronic periorbital allodynia and cephalic pain, and one NTG injection caused acute allodynia. Daily DK-I-56-1 prevented chronic allodynia and cephalic pain, and abolished acute allodynia in both sexes. Anti-allodynic and cephalic pain-relieving effects of DK-I-56-1 (10 mg/kg, i.p.) were mimicked by topiramate (30 mg/kg, i.p.), antagonized by i.p. furosemide, an α6GABA_AR antagonist, and nullified in Gabra6-knockout ICR mice. However, olcegepant (1 mg/kg, i.p.) only partially prevented cephalic pain. In dissociated TG neurons, DK-I-56-1 induced a furosemide-sensitive potentiation of GABA-induced current and depolarization. However, DK-I-56-1 did not altered increased inflammatory cytokines, down-regulated glutamate decarboxylase 65 kDa (GAD65), and Gabra6 protein levels in TG of riNTG-treated mice. Therefore, DK-I-56-1 may have the potential to prevent and abort migraines by potentiating GABA-induced depolarization in TG neurons via α6GABA_ARs, offering efficacy comparable to that of topiramate but superior to olcegepant as a novel migraine therapy.

Sex‐dependent vascular effects of transient receptor potential (TRP) channels and sex dimorphism in migraine are not yet fully characterized. We investigated the differential vasoactive effects of TRP ankyrin 1 (TRPA1), TRP melastatin 3 (TRPM3) and TRP vanilloid 1 (TRPV1) channels, their pharmacological mechanism(s), and localization and expression in human isolated blood vessels.

Agonist responses to cinnamaldehyde (TRPA1), pregnenolone sulfate (PregS, TRPM3) or capsaicin (TRPV1) were analysed using wire myography in segments of human coronary (HCAs) and middle meningeal (HMMAs) arteries from men and women. The mechanisms involved in these responses were investigated using the antagonists/blockers/inhibitors: HC‐030031 (TRPA1), isosakuranetin (TRPM3), capsazepine (TRPV1), olcegepant (calcitonin gene‐related peptide [CGRP] receptor), L‐NAME (nitric oxide synthase [NOS]), indomethacin (cyclooxygenase [COX]), TRAM‐34 + apamin (K+ channels) or MK‐801 (N‐methyl‐d‐aspartate [NMDA] receptor). Fluorescence microscopy, quantitative polymerase chain reaction (qPCR), and western blotting were performed to investigate their location and expression, respectively.

In HCAs and HMMAs, (i) capsaicin‐induced relaxation remained unchanged after the above‐mentioned antagonists/blockers/inhibitors and (ii) cinnamaldehyde‐induced relaxation was blocked by olcegepant. PregS‐induced maximal relaxation was significantly enhanced in isolated arteries from females compared with males and was inhibited after isosakuranetin, MK‐801 or L‐NAME. TRPM3 mRNA and protein expression, along with NMDA protein levels, were higher in arteries from females than males.

Modulation of vascular tone in HCAs and HMMAs by activation of TRPM3 is sex‐dependent, likely involving NMDA receptors. This represents a new therapeutic direction, targeting sex dimorphism in migraine and its related cardiovascular events.