PMID- 30016665
OWN - NLM
STAT- MEDLINE
DCOM- 20190220
LR  - 20210109
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Print)
IS  - 0028-3908 (Linking)
VI  - 140
DP  - 2018 Sep 15
TI  - The alpha6 subunit-containing GABA(A) receptor: A novel drug target for inhibition of 
      trigeminal activation.
PG  - 1-13
LID - S0028-3908(18)30378-2 [pii]
LID - 10.1016/j.neuropharm.2018.07.017 [doi]
AB  - Novel treatments against migraine are an urgent medical requirement. The alpha6 
      subunit-containing GABA(A) receptors (alpha6GABA(A)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 
      alpha6GABA(A)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 alpha6GABA(A)R-selective 
      positive allosteric modulator (PAM), the pyrazoloquinolinone Compound 6, two 
      alpha6GABA(A)R-active PAMs (Ro15-4513 and loreclezole), an alpha6GABA(A)R-inactive 
      benzodiazepine (diazepam), an alpha6GABA(A)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 alpha6GABA(A)R in TG is a novel drug target for TGVS activation and 
      that alpha6GABA(A)R-selective PAMs have the potential to be developed as a novel 
      pharmacotherapy for migraine.
CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
FAU - Fan, Pi-Chuan
AU  - Fan PC
AD  - Department of Pediatrics, College of Medicine, National Taiwan University, 
      Taipei, 10051, Taiwan; Department of Pediatrics, National Taiwan University 
      Hospital, Taipei, 10002, Taiwan; Clinical Center for Neuroscience and Behavioral, 
      National Taiwan University Hospital, Taipei, 10002, Taiwan.
FAU - Lai, Tzu-Hsuan
AU  - Lai TH
AD  - Department of Pediatrics, National Taiwan University Hospital, Taipei, 10002, 
      Taiwan.
FAU - Hor, Chia Chun
AU  - Hor CC
AD  - Graduate Institute of Pharmacology, College of Medicine, National Taiwan 
      University, Taipei, 10051, Taiwan.
FAU - Lee, Ming Tatt
AU  - Lee MT
AD  - Graduate Institute of Brain and Mind Sciences, College of Medicine, National 
      Taiwan University, Taipei, 10051, Taiwan; Faculty of Pharmaceutical Sciences, 
      UCSI University, Kuala Lumpur, Malaysia.
FAU - Huang, Pokai
AU  - Huang P
AD  - Department of Pediatrics, E-da Dachang Hospital, Kaohsiung, 807, Taiwan.
FAU - Sieghart, Werner
AU  - Sieghart W
AD  - Center for Brain Research, Department of Molecular Neurosciences, Medical 
      University Vienna, Vienna, 1090, Wien, Austria.
FAU - Ernst, Margot
AU  - Ernst M
AD  - Center for Brain Research, Department of Molecular Neurosciences, Medical 
      University Vienna, Vienna, 1090, Wien, Austria.
FAU - Knutson, Daniel E
AU  - Knutson DE
AD  - Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 
      Milwaukee, Wisconsin, WI, 53211, USA.
FAU - Cook, James
AU  - Cook J
AD  - Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 
      Milwaukee, Wisconsin, WI, 53211, USA.
FAU - Chiou, Lih-Chu
AU  - Chiou LC
AD  - 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; Clinical 
      Center for Neuroscience and Behavioral, National Taiwan University Hospital, 
      Taipei, 10002, Taiwan; Graduate Institute of Acupuncture Sciences, China Medical 
      University, Taichung, 404, Taiwan. Electronic address: lcchiou@ntu.edu.tw.
LA  - eng
GR  - R01 NS076517/NS/NINDS NIH HHS/United States
GR  - R01 MH096463/MH/NIMH NIH HHS/United States
GR  - R01 HL118561/HL/NHLBI NIH HHS/United States
GR  - I 2306/FWF_/Austrian Science Fund FWF/Austria
GR  - R43 MH083417/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180721
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Azides)
RN  - 0 (GABA-A Receptor Agonists)
RN  - 0 (GABA-A Receptor Antagonists)
RN  - 0 (PZ-II-029)
RN  - 0 (Pyrazolones)
RN  - 0 (Quinolones)
RN  - 0 (Receptors, GABA-A)
RN  - 0 (Triazoles)
RN  - 0H73WJJ391 (Topiramate)
RN  - 12794-10-4 (Benzodiazepines)
RN  - 6DJ32STZ5W (loreclezole)
RN  - 7LXU5N7ZO5 (Furosemide)
RN  - 91917-65-6 (Ro 15-4513)
RN  - JHB2QIZ69Z (Calcitonin Gene-Related Peptide)
RN  - Q3JTX2Q7TU (Diazepam)
RN  - S07O44R1ZM (Capsaicin)
SB  - IM
MH  - Animals
MH  - Azides/pharmacology
MH  - Benzodiazepines/pharmacology
MH  - Calcitonin Gene-Related Peptide/metabolism
MH  - Capsaicin/administration & dosage/antagonists & inhibitors/pharmacology
MH  - Diazepam/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Dura Mater/metabolism
MH  - Furosemide/pharmacology
MH  - GABA-A Receptor Agonists/*pharmacology
MH  - GABA-A Receptor Antagonists/*pharmacology
MH  - Infusions, Intraventricular
MH  - Male
MH  - Pyrazolones/pharmacology
MH  - Quinolones/pharmacology
MH  - Rats
MH  - Receptors, GABA-A/*chemistry/*drug effects/metabolism
MH  - Topiramate/pharmacology
MH  - Triazoles/pharmacology
MH  - Trigeminal Ganglion/*drug effects/physiology
PMC - PMC6180911
MID - NIHMS990219
OTO - NOTNLM
OT  - Calcitonin gene-related peptide
OT  - Positive allosteric modulator
OT  - Trigeminal ganglia
OT  - Trigeminovascular activation
OT  - alpha6GABA(A)R
COIS- Conflict of Interest: The authors declare no conflicts of interest.
EDAT- 2018/07/18 06:00
MHDA- 2019/03/20 06:00
PMCR- 2019/09/15
CRDT- 2018/07/18 06:00
PHST- 2018/02/22 00:00 [received]
PHST- 2018/06/29 00:00 [revised]
PHST- 2018/07/12 00:00 [accepted]
PHST- 2018/07/18 06:00 [pubmed]
PHST- 2019/03/20 06:00 [medline]
PHST- 2018/07/18 06:00 [entrez]
PHST- 2019/09/15 00:00 [pmc-release]
AID - S0028-3908(18)30378-2 [pii]
AID - 10.1016/j.neuropharm.2018.07.017 [doi]
PST - ppublish
SO  - Neuropharmacology. 2018 Sep 15;140:1-13. doi: 10.1016/j.neuropharm.2018.07.017. 
      Epub 2018 Jul 21.