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Open AccessArticle

Anti-Epileptic Effects of FABP3 Ligand MF1 through the Benzodiazepine Recognition Site of the GABAA Receptor

Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
Department of Genomic Neurology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan
Department of Neurophysiology, Hyogo College of Medicine, Nishinomiya 663-8501, Japan
Department of Neurophysiology, Graduate School of Medicine, Hirosaki University, Hirosaki 036-8216, Japan
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(15), 5525;
Received: 14 July 2020 / Revised: 29 July 2020 / Accepted: 29 July 2020 / Published: 1 August 2020
(This article belongs to the Special Issue Precision Medicine and Therapy for Neurodegenerative Disorders)
Recently, we developed the fatty acid-binding protein 3 (FABP3) ligand MF1 (4-(2-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenoxy) butanoic acid) as a therapeutic candidate for α-synucleinopathies. MF1 shows affinity towards γ-aminobutyric acid type-A (GABAA) receptor, but its effect on the receptor remains unclear. Here, we investigate the pharmacological properties of MF1 on the GABAA receptor overexpressed in Neuro2A cells. While MF1 (1–100 μm) alone failed to evoke GABA currents, MF1 (1 μm) promoted GABA currents during GABA exposure (1 and 10 μm). MF1-promoted GABA currents were blocked by flumazenil (10 μm) treatment, suggesting that MF1 enhances receptor function via the benzodiazepine recognition site. Acute and chronic administration of MF1 (0.1, 0.3 and 1.0 mg/kg, p.o.) significantly attenuated status epilepticus (SE) and the mortality rate in pilocarpine (PILO: 300 mg/kg, i.p.)-treated mice, similar to diazepam (DZP: 5.0 mg/kg, i.p.). The anti-epileptic effects of DZP (5.0 mg/kg, i.p.) and MF1 (0.3 mg/kg, p.o.) were completely abolished by flumazenil (25 mg/kg, i.p.) treatment. Pentylenetetrazol (PTZ: 90 mg/kg, i.p.)-induced seizures in mice were suppressed by DZP (5.0 mg/kg, i.p.), but not MF1. Collectively, this suggests that MF1 is a mild enhancer of the GABAA receptor and exercises anti-epileptic effects through the receptor’s benzodiazepine recognition site in PILO-induced SE models. View Full-Text
Keywords: GABAA receptor; anti-epileptic effect; benzodiazepine recognition site GABAA receptor; anti-epileptic effect; benzodiazepine recognition site
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Yabuki, Y.; Liu, J.; Kawahata, I.; Izumi, H.; Shinoda, Y.; Koga, K.; Ueno, S.; Shioda, N.; Fukunaga, K. Anti-Epileptic Effects of FABP3 Ligand MF1 through the Benzodiazepine Recognition Site of the GABAA Receptor. Int. J. Mol. Sci. 2020, 21, 5525.

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