Recently, we developed the fatty acid-binding protein 3 (FABP3) ligand MF1\n(4-(2-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenoxy) butanoic acid) as a therapeutic\ncandidate for Alpha-synucleinopathies. MF1 shows affnity towards \n-aminobutyric acid type-A (GABAA)\nreceptor, but its effect on the receptor remains unclear. Here, we investigate the pharmacological\nproperties of MF1 on the GABAA receptor overexpressed in Neuro2A cells. While MF1 \nalone failed to evoke GABA currents, MF1 promoted GABA currents during GABA exposure. MF1-promoted GABA currents were blocked by flumazenil treatment, suggesting\nthat MF1 enhances receptor function via the benzodiazepine recognition site. Acute and chronic\nadministration of MF1 (0.1, 0.3 and 1.0 mg/kg, p.o.) significantly attenuated status epilepticus (SE)\nand the mortality rate in pilocarpine (PILO: 300 mg/kg, i.p.)-treated mice, similar to diazepam (DZP:\n5.0 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\ncompletely abolished by flumazenil (25 mg/kg, i.p.) treatment. Pentylenetetrazol (PTZ: 90 mg/kg,\ni.p.)-induced seizures in mice were suppressed by DZP (5.0 mg/kg, i.p.), but not MF1. Collectively,\nthis suggests that MF1 is a mild enhancer of the GABAA receptor and exercises anti-epileptic effects\nthrough the receptorâ??s benzodiazepine recognition site in PILO-induced SE models.
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