• Natural Product Sciences
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• v.22 no.4
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• pp.263-269
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• 2016

Rhynchophylline (RP) is a major tetracyclic oxindole alkaloid of Uncariae Ramulus et Uncus which has been used to treat hypertension, seizures, pain and anxiety in the oriental countries. A recent report revealed that RP attenuated ischemia-induced neuronal damage and kainite-induced convulsions in animals. This study was performed to investigate whether RP enhances pentobarbital-induced sleep behaviors and modulates sleep architecture in mice. Locomotor activity was significantly inhibited by RP at 0.25 and 0.5 mg/kg, similar to 2 mg/kg diazepam (a benzodiazepine agonist) in mice. RP shortened sleep latency and increased total sleep time in a dose-dependent manner when administrated with pentobarbital (42 mg/kg, i.p.). RP also increased the number of sleeping mice and total sleep time by concomitant administration with the sub-hypnotic dosage of pentobarbital (28 mg/kg, i.p.). On the other hand, RP (0.25 mg/kg, p.o.) itself significantly inhibited sleep-wake cycles, prolonged total sleep time, and rapid eye movement in rats. In addition, RP also increased chloride influx in the primary cultured hypothalamic neuronal cells. In addition, we found that glutamic acid decarboxylase ($GAD_{65/67}$) was activated by RP. In conclusion, RP augments pentobarbital-induced sleeping behaviors, and can be a candidate for treating insomnia.

• Journal of Physiology & Pathology in Korean Medicine
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• v.24 no.4
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• pp.598-601
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• 2010

This experiment was performed to investigate whether the combined-preparation of water extracts of germinated brown rice (WGR), water extracts of cultured mountain ginseng (WCG) and 70% ethanol extracts of Longanae Arillus (ELA) has hypnotic effects and/or enhances pentobarbital-induced sleep behaviors through the GABAergic system. The combined-preparation of WGR and WCG reduced sleep latency and prolonged sleep time induced by pentobarbital. ELA also reduced sleep latency and prolonged sleep time induced by pentobarbital. However, WGR or WCG itself did not induce sleep. The combined-preparation of WGR, WCG and ELA strongly reduced sleep latency and prolonged sleep time via chloride influx into primary cultured cerebellar granule cells. In conclusion, the combined-preparation of WGR, WCG and ELA augments pentobarbital-induced sleep behaviors through the modification of GABAergic system.

• Natural Product Sciences
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• v.23 no.1
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• pp.53-60
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• 2017

Perillae Herba has been traditionally used for the sedation in the oriental countries. Therefore, this study was conducted to determine whether Perillae Herba ethanol extract (PHEE) enhances pentobarbital-induced sleeping behaviors in animals. In addition, the possible mechanisms are demonstrated. PHEE (12.5, 25 and 50 mg/kg. p.o.) reduced the locomotor activity in mice. PHEE reduced sleep latency and augmented the total sleep time in pentobarbital (42 mg/kg, i.p.)-induced sleep in mice. Furthermore, the number of sleeping mice treated with sub-hypnotic pentobarbital (28 mg/kg, i.p.) increased. PHEE (50 mg/kg. p.o.) decreased the sleep/wake cycles and wakefulness, and increased total sleeping time and NREM sleep in electroencephalogram (EEG) of rats. In addition, PHEE (0.1, 1.0 and $10{\mu}g/ml$) increased the intracellular $Cl^-$ level through the GABA receptors in the hypothalamus of rats. Moreover, the protein of glutamate decarboxylase (GAD) was overexpressed by PFEE. It was found that PHEE enhanced pentobarbital-induced sleeping behaviors through $GABA_A-ergic$ transmissions.

• Natural Product Sciences
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• v.18 no.2
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• pp.67-75
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• 2012

Zizyphi Spinosi Semen (ZSS) have been widely used for the treatment of insomnia in Asia. This experiment was performed to investigate whether methanol extract of ZSS (MEZSS) has hypnotic effects through the ${\gamma}$-amino butyric acid (GABA)ergic systems. MEZSS inhibited the locomotor activity. MEZSS enhanced pentobarbital-induced sleep behaviors. However, MEZSS itself did not induce sleep at higher dose, similar to muscimol. On the other hand, both pentobarbital and MEZSS increased the non rapid eye move (NREM) sleep, especially reducing the -wave electroencephalogram (EEG) activity in REM sleep. MEZSS showed similar effects with muscimol on potentiating chloride influx induced by pentobarbital. MEZSS significantly increased GABAA receptors ${\gamma}$-subunit expression and slightly decreased ${\beta}$-subunit expression in hypothalamus and thalamus, showing that subunit-expression was similar to diazepam. In addition, MEZSS enhanced the expression of glutamic acid decarboxylase (GAD). In conclusion, it is suggested that MEZSS might augment pentobarbital-induced sleep behaviors through the modification of GABAergic systems.

• Biomolecules & Therapeutics
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• v.25 no.2
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• pp.105-111
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• 2017

It has been known that RA, one of major constituents of Perilla frutescens which has been used as a traditional folk remedy for sedation in oriental countries, shows the anxiolytic-like and sedative effects. This study was performed to know whether RA may enhance pentobarbital-induced sleep through ${\gamma}-aminobutyric$ acid $(GABA)_A-ergic$ systems in rodents. RA (0.5, 1.0 and 2.0 mg/kg, p.o.) reduced the locomotor activity in mice. RA decreased sleep latency and increased the total sleep time in pentobarbital (42 mg/kg, i.p.)-induced sleeping mice. RA also increased sleeping time and number of falling sleep mice after treatment with sub-hypnotic pentobarbital (28 mg/kg, i.p.). In electroencephalogram (EEG) recording, RA (2.0 mg/kg) not only decreased the counts of sleep/wake cycles and REM sleep, but also increased the total and NREM sleep in rats. The power density of NREM sleep showed the increase in ${\delta}-waves$ and the decrease in ${\alpha}-waves$. On the other hand, RA (0.1, 1.0 and $10{\mu}g/ml$) increased intracellular $Cl^-$ influx in the primary cultured hypothalamic cells of rats. RA (p.o.) increased the protein expression of glutamic acid decarboxylase ($GAD_{65/67}$) and $GABA_A$ receptors subunits except ${\beta}1$ subunit. In conclusion, RA augmented pentobarbital-induced sleeping behaviors through $GABA_A-ergic$ transmission. Thus, it is suggested that RA may be useful for the treatment of insomnia.

• Natural Product Sciences
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• v.19 no.2
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• pp.179-185
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• 2013

Polygalae radix (PR) has traditionally been used as a sedative and anti-stress agent in oriental countries for a long time. PR which contains many ingredients is especially rich in saponins. This study was performed to investigate whether ethanol extract of PR enhances pentobarbital-induced sleep behaviors. In addition, possible mechanisms also were investigated. PR inhibited locomotor activity in mice. PR increased sleep rate and sleep time by concomitant administration with sub-hypnotic dose of pentobarbital (28 mg/kg). PR prolonged total sleeping time, and shortened sleep latency induced by pentobarbital (42 mg/kg). In addition, PR increased intracellular chloride concentration in primary cultured neuronal cells. The expression level of glutamic acid decarboxylase (GAD) were increased, and ${\gamma}$-aminobutyric acid $(GABA)_A$ receptors subunits were modulated by PR, especially increasing ${\gamma}$-subunit expression. In conclusion, PR augments penobarbital-induced sleep behaviors through activation of $GABA_A$ receptors and chloride channel complex.

• Biomolecules & Therapeutics
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• v.25 no.6
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• pp.586-592
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• 2017

Sinomenium acutum has been long used in the preparations of traditional medicine in Japan, China and Korea for the treatment of various disorders including rheumatism, fever, pulmonary diseases and mood disorders. Recently, it was reported that Sinomenium acutum, has sedative and anxiolytic effects mediated by GABA-ergic systems. These experiments were performed to investigate whether sinomenine (SIN), an alkaloid derived from Sinomenium acutum enhances pentobarbital-induced sleep via ${\gamma}$-aminobutyric acid (GABA)-ergic systems, and modulates sleep architecture in mice. Oral administration of SIN (40 mg/kg) markedly reduced spontaneous locomotor activity, similar to diazepam (a benzodiazepine agonist) in mice. SIN shortened sleep latency, and increased total sleep time in a dose-dependent manner when co-administrated with pentobarbital (42 mg/kg, i.p.). SIN also increased the number of sleeping mice and total sleep time by concomitant administration with the sub-hypnotic dosage of pentobarbital (28 mg/kg, i.p.). SIN reduced the number of sleep-wake cycles, and increased total sleep time and non-rapid eye movement (NREM) sleep. In addition, SIN also increased chloride influx in the primary cultured hypothalamic neuronal cells. Furthermore, protein overexpression of glutamic acid decarboxylase ($GAD_{65/67}$) and $GABA_A$ receptor subunits by western blot were found, being activated by SIN. In conclusion, SIN augments pentobarbital-induced sleeping behaviors through $GABA_A$-ergic systems, and increased NREM sleep. It could be a candidate for the treatment of insomnia.

• Natural Product Sciences
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• v.21 no.3
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• pp.219-225
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• 2015

In the previous experiments, we reported that ethanol extract of Gastrodiae Rhizoma, the dried tuber of Gastrodia ElataBlume (Orchidaceae) increased pentobarbital-induced sleeping behaviors. These experiments were undertaken to know whether 4-hydroxybenzaldehyde (4-HBD), is one of the major compounds of Gastrodiae Rhizoma increases pentobarbital-induced sleeping behaviors and changes sleep architectures via activating GABA_A-ergic systems in rodents. 4-HBD decreased locomotor activity in mice. 4-HBD increased total sleep time, and decreased of sleep onset by pentobarbital (28 mg/kg and 40 mg/kg). 4-HBD showed synergistic effects with muscimol (a GABA_A receptor agonist), shortening sleep onset and enhancing sleep time on pentobarbital-induced sleeping behaviors. On the other hand, 4-HBD (200 mg/kg, p.o.) itself significantly inhibited the counts of sleepwake cycles, and prolonged total sleep time and non-rapid eye movement (NREM) in rats. Moreover, 4-HBD increased intracellular Cl⁻ levels in the primary cultured cerebellar cells. The protein levels of glutamic acid decarboxylase (GAD) and GABA_A receptors subunits were over-expressed by 4-HBD. Consequently, these results demonstrate that 4-HBD increased NREM sleep as well as sleeping behaviors via the activation of GABA_A-ergic systems in rodents.

• Journal of Physiology & Pathology in Korean Medicine
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• v.27 no.6
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• pp.759-763
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• 2013

This experiment was performed to investigate whether 50% ethanol extracts of the combined-preparation of Longanae Arilus, Chrysanthemi Flos, Zizyphi Fructus and Ginseng Radix alba (CPE) has hypnotic effects and/or enhances pentobarbital-induced sleeping time. Locomotor activity was evaluated using a ambulometer of tilting-type. The sedative-hypnotic effects were evaluated by measuring the sleeping onset time and sleeping time in pentobarbital-treated mice 30 min. after oral administration of CPE and muscimol. The intracellular $Cl^-$ concentration of cerebellar granule cells was estimated using $Cl^-$ sensitive fluorescence probe N-(ethoxycarbonylmethyl)-6-methoxyquinolinium (MQAE). CPE (150 mg/kg) decreased the locomotor activity, but CPE itself did not induce sleep. However, CPE reduced sleeping onset and prolonged sleeping time induced by pentobarbital (42 mg/kg). In addition, CPE (2 ${\mu}g/ml$) and pentobarbital (2.5 ${\mu}M$) itself did not affect on the chloride influx in primary cultured cerebellar granule cells, but the combination of CPE and pentobarbital (2.5 ${\mu}M$) increased the chloride influx onto the cells. In conclusion, it is suggested that CPE might augment pentobarbital-induced sleep through the increase of chloride influx.

• Fisheries and Aquatic Sciences
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• v.17 no.1
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• pp.13-18
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• 2014

Sleep is vital to maintain health and well-being; however, insomnia is currently a widespread health complaint worldwide. In particular, caffeine, a psychoactive component of coffee, tea, and caffeine beverages may lead to sleep disorders such as insomnia. In this study, our primary objective was to investigate the inhibitory effect of high-purity phlorotannin preparation (HP-PRT) on caffeine-induced wakefulness. The sleep test of pentobarbital-induced mice was used as an in vivo animal model. Caffeine (50 and 100 mg/kg) showed significant arousal effects (an increase in sleep latency and a decrease in sleep duration). Co-administration of caffeine (50 mg/kg) and the sedative-hypnotic diazepam (DZP, 1 mg/kg) did not result in similar arousal activity. HP-PRT (500 mg/kg) also inhibited caffeine-induced wakefulness. Our results suggest that HP-PRT would be a useful additive for developing coffee products without the arousal effect.