Therapeutic effects of KRM-II-81, positive allosteric modulator for α2/3 subunit containing GABAA receptors, in a mouse model of Dravet syndrome
Introduction: Dravet syndrome (DS) is an intractable epilepsy syndrome concomitant with neurodevelopmental disorder that begins in infancy. DS is dominantly caused by mutations in the SCN1A gene, which encodes the α subunit of a voltage-gated Na channel. Pre-synaptic inhibitory dysfunction is regard...
| Main Authors: | , , , , , , , , , , , |
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1273633/full |
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| author | Sachiko Nakakubo Yasuyoshi Hiramatsu Takeru Goto Syuhei Kimura Masashi Narugami Midori Nakajima Yuki Ueda Hideaki Shiraishi Atsushi Manabe Dishary Sharmin James M. Cook Kiyoshi Egawa |
| author_facet | Sachiko Nakakubo Yasuyoshi Hiramatsu Takeru Goto Syuhei Kimura Masashi Narugami Midori Nakajima Yuki Ueda Hideaki Shiraishi Atsushi Manabe Dishary Sharmin James M. Cook Kiyoshi Egawa |
| author_sort | Sachiko Nakakubo |
| collection | DOAJ |
| description | Introduction: Dravet syndrome (DS) is an intractable epilepsy syndrome concomitant with neurodevelopmental disorder that begins in infancy. DS is dominantly caused by mutations in the SCN1A gene, which encodes the α subunit of a voltage-gated Na channel. Pre-synaptic inhibitory dysfunction is regarded as the pathophysiological mechanism, but an effective strategy for ameliorating seizures and behavioral problems is still under development. Here, we evaluated the effects of KRM-II-81, a newly developed positive allosteric modulator for α 2/3 subunit containing GABAA receptors (α2/3-GABAAR) in a mice model of DS both in vivo and at the neuronal level.Methods: We used knock-in mice carrying a heterozygous, clinically relevant SCN1A mutation (background strain: C57BL/6 J) as a model of the DS (Scn1aWT/A1783V mice), knock-in mouse strain carrying a heterozygous, clinically relevant SCN1A mutation (A1783V). Seizure threshold and locomotor activity was evaluated by using the hyperthermia-induced seizure paradigm and open filed test, respectively. Anxiety-like behavior was assessed by avoidance of the center region in locomotor activity. We estimated a sedative effect by the total distance traveled in locomotor activity and grip strength. Inhibitory post synaptic currents (IPSCs) were recorded from a hippocampal CA1 pyramidal neuron in an acutely prepared brain slice.Results: KRM-II-81 significantly increased the seizure threshold of Scn1aWT/A1783V mice in a dose-dependent manner. A low dose of KRM-II-81 specifically improved anxiety-like behavior of Scn1aWT/A1783V mice. A sedative effect was induced by relatively high dose of KRM-II-81 in Scn1aWT/A1783V mice, the dose of which was not sedative for WT mice. KRM-II-81 potentiated IPSCs by increasing its decay time kinetics. This effect was more prominent in Scn1aWT/A1783V mice.Discussion: Higher activation of α2/3-GABAAR by KRM-II-81 suggests a compensatory modification of post synaptic inhibitory function against presynaptic inhibitory dysfunction in Scn1aWT/A1783V. The increased sensitivity for KRM-II-81 may be relevant to the distinct dose-dependent effect in each paradigm of Scn1aWT/A1783V mice.Conclusion: Selective activation for α2/3-GABAAR by KRM-II-81 could be potential therapeutic strategy for treating seizures and behavioral problems in DS. |
| first_indexed | 2024-03-11T20:25:05Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-11T20:25:05Z |
| publishDate | 2023-10-01 |
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| spelling | doaj.art-39e51f6b8f474a7f94e1feaa261f66f62023-10-02T15:37:33ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-10-011410.3389/fphar.2023.12736331273633Therapeutic effects of KRM-II-81, positive allosteric modulator for α2/3 subunit containing GABAA receptors, in a mouse model of Dravet syndromeSachiko Nakakubo0Yasuyoshi Hiramatsu1Takeru Goto2Syuhei Kimura3Masashi Narugami4Midori Nakajima5Yuki Ueda6Hideaki Shiraishi7Atsushi Manabe8Dishary Sharmin9James M. Cook10Kiyoshi Egawa11Department of Pediatrics, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, JapanDepartment of Pediatrics, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, JapanDepartment of Pediatrics, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, JapanDepartment of Pediatrics, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, JapanDepartment of Pediatrics, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, JapanDepartment of Pediatrics, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, JapanDepartment of Pediatrics, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, JapanDepartment of Pediatrics, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, JapanDepartment of Pediatrics, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, JapanDepartment of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, United StatesDepartment of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, United StatesDepartment of Pediatrics, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, JapanIntroduction: Dravet syndrome (DS) is an intractable epilepsy syndrome concomitant with neurodevelopmental disorder that begins in infancy. DS is dominantly caused by mutations in the SCN1A gene, which encodes the α subunit of a voltage-gated Na channel. Pre-synaptic inhibitory dysfunction is regarded as the pathophysiological mechanism, but an effective strategy for ameliorating seizures and behavioral problems is still under development. Here, we evaluated the effects of KRM-II-81, a newly developed positive allosteric modulator for α 2/3 subunit containing GABAA receptors (α2/3-GABAAR) in a mice model of DS both in vivo and at the neuronal level.Methods: We used knock-in mice carrying a heterozygous, clinically relevant SCN1A mutation (background strain: C57BL/6 J) as a model of the DS (Scn1aWT/A1783V mice), knock-in mouse strain carrying a heterozygous, clinically relevant SCN1A mutation (A1783V). Seizure threshold and locomotor activity was evaluated by using the hyperthermia-induced seizure paradigm and open filed test, respectively. Anxiety-like behavior was assessed by avoidance of the center region in locomotor activity. We estimated a sedative effect by the total distance traveled in locomotor activity and grip strength. Inhibitory post synaptic currents (IPSCs) were recorded from a hippocampal CA1 pyramidal neuron in an acutely prepared brain slice.Results: KRM-II-81 significantly increased the seizure threshold of Scn1aWT/A1783V mice in a dose-dependent manner. A low dose of KRM-II-81 specifically improved anxiety-like behavior of Scn1aWT/A1783V mice. A sedative effect was induced by relatively high dose of KRM-II-81 in Scn1aWT/A1783V mice, the dose of which was not sedative for WT mice. KRM-II-81 potentiated IPSCs by increasing its decay time kinetics. This effect was more prominent in Scn1aWT/A1783V mice.Discussion: Higher activation of α2/3-GABAAR by KRM-II-81 suggests a compensatory modification of post synaptic inhibitory function against presynaptic inhibitory dysfunction in Scn1aWT/A1783V. The increased sensitivity for KRM-II-81 may be relevant to the distinct dose-dependent effect in each paradigm of Scn1aWT/A1783V mice.Conclusion: Selective activation for α2/3-GABAAR by KRM-II-81 could be potential therapeutic strategy for treating seizures and behavioral problems in DS.https://www.frontiersin.org/articles/10.3389/fphar.2023.1273633/fullDravet syndromemouse modelantiseizurepositive allosteric modulator for α2/3 subunit containing GABA A receptoranxiolytics |
| spellingShingle | Sachiko Nakakubo Yasuyoshi Hiramatsu Takeru Goto Syuhei Kimura Masashi Narugami Midori Nakajima Yuki Ueda Hideaki Shiraishi Atsushi Manabe Dishary Sharmin James M. Cook Kiyoshi Egawa Therapeutic effects of KRM-II-81, positive allosteric modulator for α2/3 subunit containing GABAA receptors, in a mouse model of Dravet syndrome Frontiers in Pharmacology Dravet syndrome mouse model antiseizure positive allosteric modulator for α2/3 subunit containing GABA A receptor anxiolytics |
| title | Therapeutic effects of KRM-II-81, positive allosteric modulator for α2/3 subunit containing GABAA receptors, in a mouse model of Dravet syndrome |
| title_full | Therapeutic effects of KRM-II-81, positive allosteric modulator for α2/3 subunit containing GABAA receptors, in a mouse model of Dravet syndrome |
| title_fullStr | Therapeutic effects of KRM-II-81, positive allosteric modulator for α2/3 subunit containing GABAA receptors, in a mouse model of Dravet syndrome |
| title_full_unstemmed | Therapeutic effects of KRM-II-81, positive allosteric modulator for α2/3 subunit containing GABAA receptors, in a mouse model of Dravet syndrome |
| title_short | Therapeutic effects of KRM-II-81, positive allosteric modulator for α2/3 subunit containing GABAA receptors, in a mouse model of Dravet syndrome |
| title_sort | therapeutic effects of krm ii 81 positive allosteric modulator for α2 3 subunit containing gabaa receptors in a mouse model of dravet syndrome |
| topic | Dravet syndrome mouse model antiseizure positive allosteric modulator for α2/3 subunit containing GABA A receptor anxiolytics |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1273633/full |
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