Anti-Epileptic Effects of FABP3 Ligand MF1 through the Benzodiazepine Recognition Site of the GABAA Receptor
Anti-Epileptic Effects of FABP3 Ligand MF1 through the Benzodiazepine Recognition Site of the GABAA Receptor
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DOI：
10.3390/ijms21155525
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发表时间：
2020-08
影响因子：
5.6
通讯作者：
Y. Yabuki;Jiaqi Liu;I. Kawahata;Hisanao Izumi;Yasuharu Shinoda;K. Koga;S. Ueno;N. Shioda;K. Fukunaga
中科院分区：
文献类型：
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作者：
Y. Yabuki;Jiaqi Liu;I. Kawahata;Hisanao Izumi;Yasuharu Shinoda;K. Koga;S. Ueno;N. Shioda;K. Fukunaga
最近，我们开发了脂肪酸结合蛋白3（FABP 3）配体MF 1（4-（2-（1-（2-氯苯基）-5-苯基-1H-吡唑-3-基）苯氧基）丁酸）作为α-突触核蛋白病的治疗候选物。MF 1对γ-氨基丁酸A型受体（GABAA）具有亲和力，但其对受体的作用尚不清楚。在这里，我们调查的药理学特性MF 1对GABAA受体过表达的Neuro 2A细胞。MF 1（1-100 μm）单独作用不能引起GABA电流，而MF 1（1 μm）在GABA暴露期间（1和10 μm）促进GABA电流。MF 1促进的GABA电流被氟马西尼（10 μm）阻断，表明MF 1通过苯二氮卓类识别位点增强受体功能。急性和慢性施用MF 1（0.1、0.3和1.0 mg/kg，p.o.）在匹鲁卡品（PILO：300 mg/kg，i. p.）中显著减弱癫痫持续状态（SE）和死亡率。处理的小鼠，类似于地西泮（DZP：5.0 mg/kg，i. p.）。DZP（5.0 mg/kg，i.p.）和MFl（0.3mg/kg，p.o.）氟马西尼（25 mg/kg，i. p.）治疗戊四唑（PTZ：90 mg/kg，i. p.）- DZP（5.0mg/kg，i. p.）抑制小鼠诱发的癫痫发作，而不是MF 1。总的来说，这表明MF 1是GABAA受体的温和增强剂，并通过PILO诱导的SE模型中受体的苯二氮卓类识别位点发挥抗癫痫作用。
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.