PMID- 33111258 OWN - NLM STAT- MEDLINE DCOM- 20211206 LR - 20240214 IS - 1878-7479 (Electronic) IS - 1933-7213 (Print) IS - 1878-7479 (Linking) VI - 18 IP - 1 DP - 2021 Jan TI - alpha6GABA(A) Receptor Positive Modulators Alleviate Migraine-like Grimaces in Mice via Compensating GABAergic Deficits in Trigeminal Ganglia. PG - 569-585 LID - 10.1007/s13311-020-00951-1 [doi] AB - Migraine is caused by hyperactivity of the trigeminovascular system, where trigeminal ganglia (TG) play an important role. This hyperactivity might originate from an underfunctional GABAergic system in TG. To investigate this possibility, we adapted a mouse model of migraine by inducing migraine-like grimaces in male mice via repeated injections of nitroglycerin (NTG, 10 mg/kg, i.p.), once every 2 days, for up to 5 sessions. Migraine-like facial pain scores were measured using the mouse grimace scale. Repeated NTG treatments in mice caused significant increases in migraine-like grimaces that were aborted and prevented by two anti-migraine agents sumatriptan and topiramate, respectively. After 5 sessions of NTG injections, the GABA-synthesizing enzyme, 65-kDa glutamate decarboxylase (GAD65), but not the GABA transporter 1 (GAT1) or the alpha6 subunit-containing GABA(A) receptors (alpha6GABA(A)Rs), was downregulated in mouse TG tissues. Taking advantage of the unaffected TG alpha6GABA(A)R expression in NTG-treated mice, we demonstrated that an alpha6GABA(A)R-selective positive allosteric modulator (PAM), DK-I-56-1, exhibited both abortive and prophylactic effects, comparable to those of sumatriptan and topiramate, respectively, in this migraine-mimicking mouse model. The brain-impermeable furosemide significantly prevented the effects of DK-I-56-1, suggesting its peripheral site of action, likely via preventing alpha6GABA(A)R modulation in TG. Results suggest that a decreased GABA synthesis caused by the reduced GAD65 expression in TG contributes to the trigeminovascular activation in this repeated NTG-induced migraine-mimicking model and that the unaltered alpha6GABA(A)Rs in TG are potential targets for migraine treatment. Thus, alpha6GABA(A)R-selective PAMs are potential anti-migraine agents for both abortive and preventive therapies. FAU - Tzeng, Hung-Ruei AU - Tzeng HR AD - Department of Pharmacology, Graduate Institute of Pharmacology College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd., Section 1, 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. AD - Faculty of Pharmaceutical Sciences, UCSI University, 56000, Kuala Lumpur, Malaysia. FAU - Fan, Pi-Chuan AU - Fan PC AD - Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan. AD - Department of Pediatrics, National Taiwan University Hospital, Taipei, 10002, Taiwan. FAU - Knutson, Daniel E AU - Knutson DE AD - Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, USA. FAU - Lai, Tzu-Hsuan AU - Lai TH AD - Department of Pediatrics, National Taiwan University Hospital, Taipei, 10002, Taiwan. FAU - Sieghart, Werner AU - Sieghart W AD - Center for Brain Research, Department of Molecular Neurosciences, Medical University Vienna, 1090, Vienna, Austria. FAU - Cook, James AU - Cook J AD - Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, USA. FAU - Chiou, Lih-Chu AU - Chiou LC AUID- ORCID: 0000-0001-5356-940X AD - Department of Pharmacology, Graduate Institute of Pharmacology College of Medicine, National Taiwan University, No. 1, Jen-Ai Rd., Section 1, Taipei, 10051, Taiwan. lcchiou@ntu.edu.tw. AD - Graduate Institute of Brain and Mind Sciences College of Medicine, National Taiwan University, Taipei, 10051, Taiwan. lcchiou@ntu.edu.tw. AD - Graduate Institute of Acupuncture Science, China Medical University, Taichung, 40402, Taiwan. 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 - R01NS076517, R01MH096463/NH/NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20201027 PL - United States TA - Neurotherapeutics JT - Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics JID - 101290381 RN - 0 (GABA Plasma Membrane Transport Proteins) RN - 0 (Gabra6 protein, mouse) RN - 0 (Receptors, GABA-A) RN - 0 (Slc6a1 protein, mouse) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - EC 4.1.1.15 (Glutamate Decarboxylase) RN - EC 4.1.1.15 (glutamate decarboxylase 2) RN - G59M7S0WS3 (Nitroglycerin) SB - IM MH - Animals MH - Disease Models, Animal MH - Fluorescent Antibody Technique MH - GABA Plasma Membrane Transport Proteins/metabolism MH - Glutamate Decarboxylase/metabolism MH - Male MH - Mice MH - Mice, Inbred ICR MH - Migraine Disorders/chemically induced/*drug therapy MH - Nitroglycerin/pharmacology MH - Pain Measurement MH - Receptors, GABA-A/*drug effects/metabolism MH - Trigeminal Ganglion/*drug effects/pathology MH - gamma-Aminobutyric Acid/metabolism PMC - PMC8116449 OTO - NOTNLM OT - 65-kDa glutamate decarboxylase OT - GABA transporter 1. OT - Migraine OT - mouse grimace scale OT - nitroglycerin OT - trigeminal ganglia OT - alpha6 subunit-containing GABAA receptor COIS- HRT, MTL, and THL declare no conflict of interest. A patent application has been jointly filed by PCF, DEK, JC, WS, and LCC as inventors for the composition and use patents of alpha6GABA(A)R-modulating pyrazoloquinolinone compounds for multiple indications. The patent right is co-owned by the inventors' institutions. EDAT- 2020/10/29 06:00 MHDA- 2021/12/15 06:00 PMCR- 2022/01/01 CRDT- 2020/10/28 05:44 PHST- 2020/10/10 00:00 [accepted] PHST- 2020/10/29 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2020/10/28 05:44 [entrez] PHST- 2022/01/01 00:00 [pmc-release] AID - S1878-7479(23)01217-5 [pii] AID - 951 [pii] AID - 10.1007/s13311-020-00951-1 [doi] PST - ppublish SO - Neurotherapeutics. 2021 Jan;18(1):569-585. doi: 10.1007/s13311-020-00951-1. Epub 2020 Oct 27.