$ α6GABA_{A} $ Receptor Positive Modulators Alleviate Migraine-like Grimaces in Mice via Compensating GABAergic Deficits in Trigeminal Ganglia
Abstract 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 α6 subunit-containing $ GABA_{A} $ receptors ($ α6GABA_{A} $Rs), was downregulated in mouse TG tissues. Taking advantage of the unaffected TG $ α6GABA_{A} $R expression in NTG-treated mice, we demonstrated that an $ α6GABA_{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 $ α6GABA_{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 $ α6GABA_{A} $Rs in TG are potential targets for migraine treatment. Thus, $ α6GABA_{A} $R-selective PAMs are potential anti-migraine agents for both abortive and preventive therapies..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:18 |
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| Enthalten in: |
Neurotherapeutics - 18(2020), 1 vom: 27. Okt., Seite 569-585 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tzeng, Hung-Ruei [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Anmerkungen: |
© The American Society for Experimental NeuroTherapeutics, Inc. 2020 |
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| doi: |
10.1007/s13311-020-00951-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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OLC2125445379 |
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| 520 | |a Abstract 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 α6 subunit-containing $ GABA_{A} $ receptors ($ α6GABA_{A} $Rs), was downregulated in mouse TG tissues. Taking advantage of the unaffected TG $ α6GABA_{A} $R expression in NTG-treated mice, we demonstrated that an $ α6GABA_{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 $ α6GABA_{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 $ α6GABA_{A} $Rs in TG are potential targets for migraine treatment. Thus, $ α6GABA_{A} $R-selective PAMs are potential anti-migraine agents for both abortive and preventive therapies. | ||
| 700 | 1 | |a Lee, Ming Tatt |4 aut | |
| 700 | 1 | |a Fan, Pi-Chuan |4 aut | |
| 700 | 1 | |a Knutson, Daniel E. |4 aut | |
| 700 | 1 | |a Lai, Tzu-Hsuan |4 aut | |
| 700 | 1 | |a Sieghart, Werner |4 aut | |
| 700 | 1 | |a Cook, James |4 aut | |
| 700 | 1 | |a Chiou, Lih-Chu |0 (orcid)0000-0001-5356-940X |4 aut | |
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