α6GABAA receptor positive allosteric modulators targeting trigeminal ganglia for preventing and aborting chronic periorbital allodynia and cephalic pain in both sexes: A mechanistic and comparative preclinical study

  • Biomed Pharmacother. 2025 Aug:189:118344. doi: 10.1016/j.biopha.2025.118344.
Xin-Chen Chang  1 ,  Chen-Jiun Yeh  1 ,  Yi-Ting Pan  1 ,  Yueh-Peng Chen  2 ,  Dishary Sharmin  3 ,  James Cook  3 ,  Yu-Cheng Pei  4 ,  Lih-Chu Chiou  5
Affiliations
  • 1. Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
  • 2. Master of Science Degree Program in Innovation for Smart Medicine, Chang Gung University, Taoyuan City 333, Taiwan; Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital at Linkou, Taoyuan City 333, Taiwan.
  • 3. Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA.
  • 4. Master of Science Degree Program in Innovation for Smart Medicine, Chang Gung University, Taoyuan City 333, Taiwan; Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital at Linkou, Taoyuan City 333, Taiwan.
  • 5. Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan; Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan; Graduate Institute of Acupuncture Science, China Medical University, Taichung 40402, Taiwan. Electronic address: [email protected].
PMID: 40652726 DOI: 10.1016/j.biopha.2025.118344
Abstract

Migraine remains an unmet medical need, even with new Calcitonin gene-related peptide (CGRP)-targeting treatments. The α6 subunit (Gabra6)-containing GABAA receptors (α6GABAARs) are abundant in trigeminal ganglia (TG). We evaluated the possible anti-migraine efficacy and mechanism of DK-I-56-1, a druggable α6GABAAR-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 α6GABAAR 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 α6GABAARs, offering efficacy comparable to that of topiramate but superior to olcegepant as a novel migraine therapy.

Keywords
CGRP; GABA(A) receptor; Migraine; Mouse grimace scale; Nitroglycerin; Periorbital allodynia; Trigeminal ganglia.
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