Although Ziziphus jujuba Mill (jujube) is used in folk medicine for hypnotic sedative, anxiolytic, and many other purposes, to date, only a few studies have revealed its sleep-promoting effects and related mechanisms. Currently, drugs used for the treatment of sleep disorders have various side effects, so it is essential to develop safe natural materials. Therefore, we evaluated the sleep-enhancing activity and mechanism of action of an aqueous extract of jujube seeds (ZW) fermented with Lactobacillus brevis L-32 in rodent models. The starch contained in ZW was removed by enzymatic degradation and fermented with L. brevis to obtain a fermented product (ZW-FM) with a high γ-aminobutyric acid (GABA) content. To evaluate the sleep-promoting effect of ZW-FM, pentobarbital-induced sleep tests were performed on ICR mice, and electroencephalography analysis was undertaken in Sprague Dawley rats. Additionally, the awakening relief effects of ZW-FM were confirmed in a caffeine-induced insomnia model. Finally, the mechanism of sleep enhancement by ZW-FM was analyzed using GABA receptor type A (GABAA) antagonists. The ZW-FM-treated groups (100 and 150 mg/kg) showed increased sleep time, especially the δ-wave time during non-rapid eye movement (NREM) sleep. In addition, the 150 mg/kg ZW-FM treatment group showed decreased sleep latency and increased sleep time in the insomnia model. In particular, NREM sleep time was increased and REM sleep time, which was increased by caffeine treatment, was decreased by ZW-FM treatment. ZW-FM-induced sleep increase was inhibited by the GABAA receptor antagonists picrotoxin, bicuculline, and flumazenil, confirming that the increase was the result of a GABAergic mechanism. These results strongly suggest that the increased GABA in water extract from jujube seeds fermented by L. brevis acts as a sleep-promoting compound and that the sleep-promoting activity is related to GABAA receptor binding.
Keywords: GABAA receptor; Zizyphus jujuba; enzymatic hydrolysis; fermentation; sleep.