Novel neuropharmacological activity of citrus lime (Citrus aurantifolia): A standardized lime peel supplement enhances non-rapid eye movement sleep by activating the GABA type A receptor

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Polyphenols have been well-established to exert sedative-hypnotic effects in psychopharmacology. Lime ( Citrus aurantifolia ) peel is rich in biologically active polyphenols; however, the effects of lime peel extract on sleep have not yet been demonstrated. A comparison was conducted in mice, between the sleep-promoting effects of a standardized lime peel supplement (SLPS) and a well-known hypnotic drug, zolpidem, and its hypnotic mechanism was investigated using in vivo and in vitro assays. The effects of SLPS on sleep were assessed using a pentobarbital-induced sleep test and sleep architecture analysis based on recording electroencephalograms and electromyograms. Additionally, a GABA A receptor binding assay, electrophysiological measurements, and in vivo animal models were used to elucidate the hypnotic mechanism. SLPS (200 and 400 mg/kg) was found to significantly decrease sleep latency and increase the amount of non-rapid eye movement sleep without altering delta activity. The hypnotic effects of SLPS were attributed to its flavonoid-rich ethyl acetate fraction. SLPS had a binding affinity to the GABA-binding site of the GABA A receptor and directly activated the GABA A receptors. The hypnotic effects and GABA A receptor activity of SLPS were completely blocked by bicuculline, a competitive antagonist of the GABA A receptor, in both in vitro and in vivo assays. To the best of our knowledge, this study is the first to demonstrate the hypnotic effects of SLPS, which acts via the GABA-binding site of the GABA A receptor. Our results suggest that lime peel, a by-product abundantly generated during juice processing, can potentially be used as a novel sedative-hypnotic. • SLPS accelerated sleep in mice treated with pentobarbital. • SLPS (100–400 mg/kg) dose-dependently increased non-rapid eye movement sleep. • The flavonoid-rich ethyl acetate fraction from SLPS exerted hypnotic effects. • SLPS activated the GABA A receptors as an agonist to their GABA-binding site. • Sleep-promoting effects of SLPS in mice were inhibited by bicuculline.