Rosmarinic Acid Potentiates Pentobarbital-Induced Sleep Behaviors and Non-Rapid Eye Movement (NREM) Sleep through the Activation of GABA(A)-ergic Systems

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 γ-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 δ-waves and the decrease in α-waves. On the other hand, RA (0.1, 1.0 and 10 μg/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 β1 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.

Ethanol Extract of Perillae Herba Enhances Pentobarbital-Induced Sleep and Non-Rapid Eye Movement (NREM) Sleep through GABA(A)-ergic Systems

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 µg/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.

Sedative-Hypnotic and Receptor Binding Studies of Fermented Marine Organisms

This study was performed to investigate the sedative-hypnotic activity of gamma-aminobutyric acid (GABA)-enriched fermented marine organisms (FMO), including sea tangle (FST) and oyster (FO) by Lactobacillus brevis BJ20 (L. brevis BJ20). FST and FO were tested for their binding activity of the GABA(A)-benzodiazepine and 5-HT(2C) receptors, which are well-known molecular targets for sleep aids. We also measured the sleep latency and sleep duration during pentobarbital-induced sleep in mice after oral administration of FST and FO. In GABA(A) and 5-HT(2C) receptor binding assays, FST displayed an effective concentration-dependent binding affinity to GABA(A) receptor, similar to the binding affinity to 5-HT(2C) receptor. FO exhibited higher affinity to 5-HT(2C) receptor, compared with the GABA(A) receptor. The oral administration of FST and FO produced a dose-dependent decrease in sleep latency and increase in sleep duration in pentobarbital-induced hypnosis. The data demonstrate that FST and FO possess sedative-hypnotic activity possibly by modulating GABA(A) and 5-HT(2C) receptors. We propose that FST and FO might be effective agents for treatment of insomnia.

Behavioral effects of aqueous and dichloromethane extracts of Erythrina speciosa Andrews, Fabaceae, leaves in mice / Efeitos comportamentais do extrato aquoso bruto e fração diclorometano das folhas de Erythrina speciosa Andrews, Fabaceae, em camundongos

Erythrina speciosa Andrews, Fabaceae, is used in the South of Brazil as sedative and tranquilizers. In this study, behavioral effects of aqueous (AE) and dichloromethane (DCM) extracts of E. speciosa leaves were evaluated in male mice, as well as their lethal dose 50 percent (LD50). The extracts were administered by gavage in doses ranging from 50 to 400 mg/kg 1 h before the behavioral tests. AE decreased ambulation (50, 100 and 400 mg/kg) and rearing (50 and 400 mg/kg) in the open-field but did not influence elevated plus maze, rotarod and pentobarbital-induced sleep tests. No behavioral effects were observed after DCM administration. LD50 for both extracts were higher than 2000 mg/kg. The results showed that AE and DCM extracts of E. speciosa leaves do not produce anxiolytic effect in the elevated plus maze nor seems to depress the Central Nervous System. However, since serotonergic mechanisms may be involved in the pharmacological action of Erythrina plants and the elevated plus maze test is not adequate to evaluate serotonergic drugs, our results do not invalidate the use of this plant in folk medicine but suggest that the mechanism involved in a possible central action of Erythrina needs to be clarified.

Erythrina speciosa Andrews, Fabaceae, é usada na região Sul do Brasil como sedativa e tranquilizante. Neste estudo, uma possível ação central do extrato aquoso (EA) e fração diclorometano (DCM) das folhas da E. speciosa foi avaliada em camundongos machos submetidos a testes comportamentais 1 h após o tratamento (gavage). Também foi avaliada a dose letal 50 por cento (DL50) como indicativa da toxicidade aguda desta planta. O EA diminuiu a locomoção (50, 100 e 400 mg/kg) e o levantar (50 e 400 mg/kg) no teste de campo aberto mas não alterou nenhum dos comportamentos avaliados nos testes de labirinto em cruz elevado, rotarod e sono induzido. A DCM não alterou nenhum dos comportamentos avaliados. A DL50 de ambos os extratos foi estimada como sendo >2000 mg/kg. Os resultados sugerem ausência de efeito ansiolítico e depressor do Sistema Nervoso Central das folhas de E. speciosa. Entretanto, como mecanismos serotonérgicos podem estar envolvidos na ação farmacológica de plantas do gênero Erythrina e o teste de labirinto em cruz elevado não é adequado para avaliar o efeito de drogas serotonérgicas, nossos resultados não invalidam o uso desta planta na medicina popular, mas apontam a necessidade de se investigar o mecanismo de ação envolvido no possível efeito central de plantas do gênero Erythrina.