Sedative-hypnotic Effects Research Articles

Hydroalcoholic Extract of Cuscuta Epithymum Enhances Pentobarbitalinduced Sleep: Possible Involvement of GABAergic System.

Insomnia is the most common sleep disorder. The present study was undertaken to evaluate the sedative-hypnotic potential of hydroalcoholic extract (HAE) of Cuscuta epithymum and its fractions. HAE and its fractions including: water fraction (WF), ethyl acetate fraction (EAF) and n-hexan fraction (NHF) were i.p administered to male mice and 30 min later pentobarbital (30 mg/kg, i.p.) was injected to induce sleep. Then the latent period and continuous sleeping time were recorded. Besides, 30 mins after administration of HAE motor coordination (rota-rod test) were assessed. Additionally, LD50 of HAE was determined and the possible neurotoxicity of the extract was tested on neural PC12 cells. The HAE and NHF decreased the latency of sleep and significantly increased the duration of sleep induced by pentobarbital. These effects of C. epithymum were reversed by flumazenil. HAE did not affect the animals' performance on the rotarod test. The LD50 value for HAE was found to be 4.8 g/kg. HAE and its fractions had no toxicity effect on the viability of PC12-cell line. The results of the present study indicate that the HAE and NHF have significant sedativehypnotic effects in mice without major toxic effect and that the benzodiazepine receptors are involved in the sedative-hypnotic effects of this plant.

Effects of sedative-hypnotics on sleep quality among patients with insomnia: evidence from an observational, pre-post study in India

BackgroundInsomnia continues to be neglected globally, despite its high prevalence. Guidelines by the health regulatory agencies call for studies to evaluate the effect of sedative-hypnotics on sleep quality.MethodsWe conducted a pre-post observational study to evaluate sleep quality among 186 inpatients receiving short-term oral sedative-hypnotic therapy in a tertiary care teaching hospital in Kozhikode (Kerala), India. Using Pittsburgh Sleep Quality Index_Past-Week (PSQI_PW) questionnaire, patients were interviewed upon hospital admission and at follow up after ≥1-week of sedative-hypnotic therapy. Additionally, we interviewed 36 physicians to understand the current clinical perception about sedative-hypnotics.ResultsMean (SD) age of the study patients was 59 (7.5) years. Majority (63.4%) of the patients were men. Of the various primary diagnoses for hospitalization, cardiovascular disease was the most common (22.6%, n = 49). Sedative-hypnotic therapy improved the mean (SD) PSQI_PW overall score by 6.79 points (pre: 12.70 (3.5) vs. post: 5.91 (2.8); p < 0.0001). Statistically significant improvements in sleep duration, latency, efficacy, and day dysfunction were observed. Higher proportion of study patients were prescribed benzodiazepines (73.7%) compared to zolpidem (26.3%). Patients treated with zolpidem reported higher improvements in mean overall PSQI_PW scores compared to those treated with benzodiazepines, however these differences were not statistically significant upon adjusting for age, gender and primary diagnosis for hospitalization. Qualitative interviews indicate that that physicians consider zolpidem to be safer and more efficacious.ConclusionsIn our study, sedative-hypnotic therapy helped improve sleep quality among the hospitalized patients. More studies evaluating the comparative efficacy and safety of zolpidem vs. benzodiazepines – including among patient groups with varying demographic and clinical characteristics – are needed. India must develop evidence-based treatment guidelines to inform the clinical practice around the use of sedative-hypnotics.

Revealing the sedative-hypnotic effect of the extracts of herb pair Semen Ziziphi spinosae and Radix Polygalae and related mechanisms through experiments and metabolomics approach

BackgroundSemen Ziziphi spinosae and Radix Polygalae, two herbs commonly used together in Traditional Chinese Medicine for the treatment of insomnia and anxiety. The study aims to study the sedative-hypnotic effect of the active components of the herbal pair, the possible mechanisms of such effect, and related metabolic pathways in vivo.MethodsThe sedative and hypnotic effect of the active components (EI30) of the herbal pair was studied by recording influence on the proportion of sleeping within 30 min, sleep latency and sleep length of pentobarbital sodium-induced sleeping on mice. Possible mechanisms of the sedative-hypnotic effect of the active components were investigated by measuring the content of neurotransmitters in the total protein of mice brain tissue. The main chemical compounds of the herbal pair were identified by Liquid Chromatography-Mass Spectrometry (LC-MS). Serum samples of mice were studied, and related differential metabolites between the normal group and model group, and between model group and treatment group were identified by Gas Chromatography Time-Of-Flight Mass Spectrometry (GC-TOF-MS), Principal Components Analysis (PCA), and Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA).ResultsCompared with the control group, high dose EI30 group and the Clonazepam group were with significantly higher proportions of sleep within 30 min (P = 0.027 and 0.005 respectively). Compared with the control group, all of the high, medium and low dose of EI30 groups were with significantly shorter sleep latency (P < 0.01) and prolonged sleeping time (P < 0.01). The herbal pair has good sedative-hypnotic effects, although it is weaker than the effect of Clonazepam. The sedative-hypnotic effect of EI30 is possibly related to the adjustment of neurotransmitters 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) in the total protein of mice brain tissue. There are five metabolic pathways in vivo most related to the sedative-hypnotic effect of EI30, and they are biosynthesis of valine, leucine, and isoleucine, metabolism of glyceride, metabolism of alanine, aspartic acid and glutamic acid, metabolism of phenylalanine, and metabolism of cysteine and methionine.ConclusionsThis study reveals the mechanisms of sedative and hypnotic effects of herbal pair Semen Ziziphi spinosae and Radix Polygalae by using metabolomics methods. This study provides a basis for further development and utilization of this herbal pair.

Deletion of Tlr3 reduces acute tolerance to alcohol and alcohol consumption in the intermittent access procedure in male mice.

Pharmacological studies implicate toll-like receptor 3 (TLR3) signaling in alcohol drinking. We examined the role of TLR3 in behavioral responses to alcohol and GABAergic drugs by studying Tlr3 -/- mice. Because of opposing signaling between TLR3 and MyD88 pathways, we also evaluated Myd88 -/- mice. Ethanol consumption and preference decreased in male but not in female Tlr3 -/- mice during two-bottle choice every-other-day (2BC-EOD) drinking. There were no genotype differences in either sex during continuous or limited-access drinking. Null mutations in Tlr3 or Myd88 did not alter conditioned taste aversion to alcohol and had small or no effects on conditioned place preference. The Tlr3 null mutation did not alter acute alcohol withdrawal. Male, but not female, Tlr3 -/- mice took longer than wild-type littermates to recover from ataxia by ethanol or diazepam and longer to recover from sedative-hypnotic effects of ethanol or gaboxadol, indicating regulation of GABAergic signaling by TLR3. Acute functional tolerance (AFT) to alcohol-induced ataxia was decreased in Tlr3 -/- mice but was increased in Myd88 -/- mice. Thus, MyD88 and TLR3 pathways coordinately regulate alcohol consumption and tolerance to intoxicating doses of alcohol and GABAergic drugs. Despite similar alcohol metabolism and similar amounts of total alcohol consumed during 2BC and 2BC-EOD procedures in C57BL/6J mice, only 2BC-EOD drinking induced tolerance to alcohol-induced ataxia. Ataxia recovery was inversely correlated with level of drinking in wild-type and Tlr3 -/- littermates. Thus, deleting Tlr3 reduces alcohol consumption by reducing AFT to alcohol and not by altering tolerance induced by 2BC-EOD drinking.

Cortical astrocytes regulate ethanol consumption and intoxication in mice

Astrocytes are fundamental building blocks of the central nervous system. Their dysfunction has been implicated in many psychiatric disorders, including alcohol use disorder, yet our understanding of their functional role in ethanol intoxication and consumption is very limited. Astrocytes regulate behavior through multiple intracellular signaling pathways, including G-protein coupled-receptor (GPCR)-mediated calcium signals. To test the hypothesis that GPCR-induced calcium signaling is also involved in the behavioral effects of ethanol, we expressed astrocyte-specific excitatory DREADDs in the prefrontal cortex (PFC) of mice. Activating Gq-GPCR signaling in PFC astrocytes increased drinking in ethanol-naïve mice, but not in mice with a history of ethanol drinking. In contrast, reducing calcium signaling with an astrocyte-specific calcium extruder reduced ethanol intake. Cortical astrocyte calcium signaling also altered the acute stimulatory and sedative-hypnotic effects of ethanol. Astrocyte-specific Gq-DREADD activation increased both the locomotor-activating effects of low dose ethanol and the sedative-hypnotic effects of a high dose, while reduced astrocyte calcium signaling diminished sensitivity to the hypnotic effects. In addition, we found that adenosine A1 receptors were required for astrocyte calcium activation to increase ethanol sedation. These results support integral roles for PFC astrocytes in the behavioral actions of ethanol that are due, at least in part, to adenosine receptor activation.

Acute Toxicity and Sedative-hypnotic Effects of Ethanol Stem Bark Extract and Fractions of Milicia excelsa (Moraceae) in Mice

Aim: Milicia excelsa stem bark is used as sedative and for treating mental illnesses among the Hausa tribe of Northern Nigeria, but there is no scientific rationale for its use. Hence, this study investigated the oral acute toxicity and sedative potential of ethanol stem bark extract, n-hexane, ethylacetate, n-butanol and aqueous fractions of the stem bark extract in mice. The phytoconstituents in the extract and fractions were quantified. Methodology: The acute toxicity of the extract and fractions were investigated using OECD guidelines 425 of 2008. The sedative effects of the extract and fractions were investigated using pentobarbital-, and ketamine-induced sleep tests. Results and discussion: The results obtained showed that the acute toxicity of the extract and fractions were > 5000 mg/kg, suggesting that the extract and fractions may be safe. The extract, n-hexane, ethylacetate and aqueous fractions significantly (p<0.05) reduced sleep latencies, indicative of sedative effects, effective for sleep induction, while the extract and all the fractions significantly (p<0.05) prolonged the sleep durations, suggesting sedative effects, effective for sleep maintenance. Conclusion: This study therefore, concluded that the extract and fractions may be safe. The study further concluded that the sedative effect of the extract and fractions may be due to the abundance of flavonoids in the extract and fractions. Thus, providing scientific rationale for its ethnomedicinal use. However, further study may be warranted to isolate and characterize the sleep promoting bioactive principles as well as carry out GABA binding assay of the isolated compound(s) in ESB and its various fractions.

Moringa oleifera Lam Seed Oil Augments Pentobarbital-Induced Sleeping Behaviors in Mice via GABAergic Systems.

Moringa oleifera Lam. (MO), which is widely consumed as both food and herbal medicine in tropical and subtropical regions, has a wide spectrum of health benefits. Yet, whether the oil obtained from MO seeds could affect (improve) the sleep activity remains unclear. Herein, we used the locomotor activity, pentobarbital-induced sleeping, and pentetrazol-induced convulsions test to examine sedative-hypnotic effects (SHE) of MO oil (MOO) and explored the underlying mechanisms. Besides, the main components of MOO like oleic acid, β-Sitosterol, and Stigmasterol were also evaluated. The results showed that they possessed good SHE. Except for oleic acid and Stigmasterol, they could significantly elevate γ-amino butyric acid (GABA) and reduce glutamic acid (Glu) levels in the hypothalamus of mice. Moreover, SHE was blocked by picrotoxin, flumazenil, and bicuculline, except for oleic acid, which could not be antagonized by picrotoxin. Molecular mechanisms showed that MOO and β-Sitosterol significantly upregulated the amount of protein-level expression of Glu decarboxylase-65 (GAD65) and α1-subunit of GABAA receptors in the hypothalamus of mice, not affecting GAD67, γ2 subunits. These data indicated that MOO modulates sleep architectures via activation of the GABAA-ergic systems.

Targets and underlying mechanisms related to the sedative and hypnotic activities of saponin extracts from semen Ziziphus jujube.

Semen Ziziphus jujube (SZJ) has been widely consumed because it is recognized as edible in China to treat insomnia disorders. However, the underlying mechanisms and potential therapeutic targets remain obscure. SZJ-I and SZJ-II with a saponin content of 52.10% and 75.20%, respectively, were extracted from SZJ. LC-MS analysis presented quite different chemical profiles of SZJ-I and SZJ-II. Mice with p-chlorophenylalanine (PCPA)-induced insomnia were used to comparatively and systematically test the sedative-hypnotic activities of SZJ-I and SZJ-II. In vivo behavioral tests revealed that SZJ-I and SZJ-II significantly shortened the immobility time and potentiated sodium pentobarbital-induced sleep. SZJ-II with a higher saponin content showed greater potency than SZJ-I. SZJ-I and SZJ-II also protected against PCPA-triggered neuropathological damages in the brain. Concentrations of 5-hydroxytryptamine (5-HT), dopamine (DA), noradrenaline (NE), glutamate (Glu), interleukin-6 (IL-6), interleukin-1β (IL-1β), nitric oxide (NO) and prostaglandin D2 (PGD2) in plasma were significantly affected by SZJ-I and SZJ-II application. SZJ-I and SZJ-II also exhibited differential modulation of 5-hydroxytryptamine 1A (5-HT1A), 5-hydroxytryptamine 2A (5-HT2A), GABAA receptor α2 (GABAARα2), GABAA receptor α3 (GABAARα3), glutamic acid decarboxylase (GAD) 65/67, IL-6 and IL-1β expression in the hypothalamus and hippocampus. SZJ-I and SZJ-II might exert excellent sedative-hypnotic effects through multiple mechanisms that worked simultaneously. SZJ-I and especially SZJ-II are promising candidates for relieving insomnia.

Preclinical safety evaluation of ET-26 hydrochloride, a novel intravenous anesthetic agent, in beagle dogs.

ET-26 hydrochloride (ET-26HCl) is a novel etomidate analogue, approved for clinical trials, which has an effective sedative-hypnotic effect, a stable myocardial performance, and milder adrenocortical suppression than etomidate in rats and beagle dogs. Additionally, ET-26HCl showed similar hemodynamic stability as etomidate in the rat uncontrolled hemorrhagic shock model. Furthermore, ET-26HCl, in the rat lipopolysaccharide-induced sepsis model, was found to have a higher survival rate, a lower inflammatory reaction, and less organ injury. In the present study, we measured the potential adverse effects of ET-26HCl in beagle dogs in accordance with the Guidance on single- and repeated-dose toxicity published by the China Food and Drug Administration. In toxicity studies, single and repeated (14 days) intravenous doses of up to 16 mg/kg were well tolerated, with only pharmacologically related clinical signs seen in both studies. Thus, the no-observed-adverse-effect level (NOAEL) of ET-26HCl was found at 16 mg/kg/day. Toxicokinetic examination demonstrated that ET-26HCl showed a dose-dependent increase to exposure, no gender difference, and no evidence of accumulation. These results provide useful information for guiding a phase I clinical trial of ET-26HCl in healthy volunteers.

Diazepam and ethanol differently modulate neuronal activity in organotypic cortical cultures

BackgroundThe pharmacodynamic results of diazepam and ethanol administration are similar, in that each can mediate amnestic and sedative-hypnotic effects. Although each of these molecules effectively reduce the activity of central neurons, diazepam does so through modulation of a more specific set of receptor targets (GABAA receptors containing a γ-subunit), while alcohol is less selective in its receptor bioactivity. Our investigation focuses on divergent actions of diazepam and ethanol on the firing patterns of cultured cortical neurons.MethodWe used electrophysiological recordings from organotypic slice cultures derived from Sprague–Dawley rat neocortex. We exposed these cultures to either diazepam (15 and 30 µM, n = 7) or ethanol (30 and 60 mM, n = 11) and recorded the electrical activity at baseline and experimental conditions. For analysis, we extracted the episodes of spontaneous activity, i.e., cortical up-states. After separation of action potential and local field potential (LFP) activity, we looked at differences in the number of action potentials, in the spectral power of the LFP, as well as in the coupling between action potential and LFP phase.ResultsWhile both substances seem to decrease neocortical action potential firing in a not significantly different (p = 0.659, Mann–Whitney U) fashion, diazepam increases the spectral power of the up-state without significantly impacting the spectral composition, whereas ethanol does not significantly change the spectral power but the oscillatory architecture of the up-state as revealed by the Friedman test with Bonferroni correction (p < 0.05). Further, the action potential to LFP-phase coupling reveals a synchronizing effect of diazepam for a wide frequency range and a narrow-band de-synchronizing effect for ethanol (p < 0.05, Kolmogorov–Smirnov test).ConclusionDiazepam and ethanol, induce specific patterns of network depressant actions. Diazepam induces cortical network inhibition and increased synchronicity via gamma subunit containing GABAA receptors. Ethanol also induces cortical network inhibition, but without an increase in synchronicity via a wider span of molecular targets.

Shuangxia decoction alleviates p-chlorophenylalanine induced insomnia through the modification of serotonergic and immune system.

As a Traditional Chinese Medicine (TCM), Shuangxia Decoction (SXD) has been used to treat insomnia in oriental countries for more than thousands of years and it presents remarkable clinical effects. However, its active pharmacological fraction and the mechanism of sedative-hypnotic effects have not been explored. In this paper, we investigated active pharmacological fraction and revealed the detailed mechanisms underlying the sedative-hypnotic effects of SXD. It showed that SXD water extract compared to ethanol extract possessed better sedative effects on locomotion activity in normal mice and increased sleep duration in subhypnotic dose of sodium pentobarbital-treated mice. SXD alleviated p-chlorophenylalanine (PCPA) -induced insomnia by increasing the content of 5-HT in cortex [F (4, 55) = 12.67], decreasing the content of dopamine (DA) and norepinephrine (NE). Furthermore, SXD enhanced the expression of 5-HT1A and 5-HT2A receptors in hypothalamic and reduced serum levels of IL-1,TNF-α [F (5, 36) = 15.58]. In conclusion, these results indicated that SXD produced beneficial sedative and hypnotic bioactivities mediated by regulating the serotonergic and immune system.

Dieckol is a natural positive allosteric modulator of GABAA-benzodiazepine receptors and enhances inhibitory synaptic activity in cultured neurons

ABSTRACT Phlorotannin supplement (PS) is a natural hypnotic substrate that modulates γ-aminobutyric acid type A (GABAA)-benzodiazepine (BZD) receptors. However, there is a lack of functional data assessing the role of individual components of PS, such as Dieckol, as allosteric activators of GABAA receptors (GABAAR). Using the whole cell patch clamp technique, we demonstrated that PS functionally enhanced the activity of GABAA-BZD receptors in a heterologous system and in primary cultured neurons. Application of diazepam (DZP) or Dieckol (1) increased GABAAR-mediated inward current in HEK293T cells containing the α1 subunit in a dose-dependent manner, (2) which was blocked by co-treatment with the selective benzodiazepine site antagonist, flumazenil (FLZ); it also (3) increased the amplitude of GABAA-BZD receptors in primary cultured neurons, which was blocked by FLZ and (4) attenuated spontaneous activity in cultured neurons. These results indicate that PS and Dieckol act as positive allosteric activators of GABAA-BZD receptors, which might be the underlying mechanism of the sedative-hypnotic effect of PS. To our knowledge, this is the first study to directly link Dieckol-induced GABAAR activation via the BZD site binding and suppression of spontaneous neuronal activity in vitro.

English

Most of the sedative drugs cause dose-dependent depression of the central nervous system (CNS) leading to hypnosis and possibly anaesthesia, however, these agents are associated with some side effects ranging from digestive, respiratory, immune system dysfunctions, cognitive function deterioration, tolerance, and physical dependence, hence investigations of newer and safer agents is therefore imperative. The current study sought to investigate the sedative-hypnotic effects of methanolic stem bark extract of Ficus abutilifolia in mice. Phytochemical constituents and sedative-hypnotic activity of the extract were investigated. Twenty Swiss albino mice were used for the experiment, the animals were randomly divided into four groups of five mice each. The mice in groups 1 and 2 were injected with the extract at the dose of 100 and 200 mg/kg, respectively, those in group 3 were injected with xylazine at the dose rate of 10 mg/kg, while the control group 4 mice received nothing at the beginning of the experiment. All the four experimental groups were injected with ketamine at the dose rate of 100 mg/kg after 30 min, all the treatments during the experimental trial were administered intraperitoneally (IP). Phytochemical analysis of the stem bark extract revealed the presence of carbohydrates, reducing sugars, cardiac glycosides, cardinolides, steroids and triterpenes, saponins, tannins, condensed tannins and flavonoids, while, anthraquinones, anthracene derivates and alkaloids were absent. The results show no significant difference (P ≥ 0.05) on the sleep onset time between the four groups, however, statistically significant difference (P<0.05) was recorded in the sleep duration time between the groups The group pre-treated with low dose of the extract (100 mg/kg) before ketamine administration after 30 min exhibited longer sleeping duration time. The mice were sedated for some time after arousal from sleep. Conclusively, our finding suggests that methanolic stem bark extract of F. abutilifolia possess sedative-hypnotic potentials that may require further scientific elucidations. Key words: F. abutilifolia, mice, stem bark extract, sedative-hypnotic activity.

Evaluation of phytochemical constituents and sedative-hypnotic activity of the methanol leaf extract of Ficus exasperata in mice.

Background and Aim:Sedative drugs mostly cause dose-dependent depression of the central nervous system which results in hypnosis and anesthesia possibly; however, these agents are associated with some side effects ranging respiratory, digestive, immune system dysfunctions, tolerance, cognitive function deterioration, and physical dependence; hence, investigations of newer and safer agents are, therefore, imperative. The current study was aimed at investigating the sedative-hypnotic (S-H) effects of the methanol leaf extract of Ficus exasperata in mice.Materials and Methods:Phytochemical screening of the leaf extract was conducted, and S-H activity of the plant extract was evaluated. Twenty Swiss Albino mice were randomly divided into four groups of five mice each. The mice in Groups A and B were injected with the extract intraperitoneally (IP) at the dose rate of 100 and 200 mg/kg, respectively, those in Group C were injected with xylazine at the dose rate of 10 mg/kg, while Group D mice received distilled water at the dose rate of 2 ml/kg. All the four experimental groups were injected with ketamine (IP) at the dose rate of 100 mg/kg after 30 min.Results:Phytochemical analysis of the extract revealed the presence of carbohydrates, cardiac glycosides, reducing sugars, steroids and triterpenes, saponins, tannins, condensed tannins, and flavonoids, while anthraquinones, anthracene derivatives, and alkaloids were absent. Results from the S-H evaluation show no significant difference (p≥0.05) on the onset of sleep time between the four experimental groups; however, statistically significant difference (p≤0.05) was recorded in the sleep duration time between the groups treated with only ketamine and the other experimental groups pre-treated with either the extract or xylazine before ketamine administration. The group pre-treated with a high dose of the plant extract (200 mg/kg) and the treated with ketamine after 30 min exhibited longer sleeping duration time. The plant extract, xylazine and ketamine, sedated the mice for some period of time after arousal from sleep.Conclusion:Our finding suggests that methanol leaf extract of F. exasperata possesses S-H potential that may require further scientific investigations.

Whole-body spatially-resolved metabolomics method for profiling the metabolic differences of epimer drug candidates using ambient mass spectrometry imaging

Investigation of the in vivo drug action and metabolic differences of epimer drugs is challenging. Whole-body MSI analysis can visually present the stereoscopic distribution of molecules related to the interaction of drugs and organisms, and can provide more comprehensive organ-specific profiling information. Herein, we developed a whole-body spatially-resolved imaging metabolomics method based on an air flow-assisted ionisation desorption electrospray ionisation (AFADESI)-MSI system coupled with a high-resolution mass spectrometer and highly discriminating imaging software. The epimeric sedative-hypnotic drug candidates YZG-331 and YZG-330 were selected as examples, and rats administered normal or high oral doses were used. By performing multivariate statistical data-mining on the combined MSI data, organ-specific differential ions were screened. By comparing the variations in the relative contents of the drugs, their metabolites, and endogenous neurotransmitters throughout whole-body tissue sections of the rats, rich information that could potentially explain the more significant sedative-hypnotic effects of YZG-330 compared to YZG-331 was obtained. Such as the increased ratio of gamma-aminobutyric acid in the brain and stomach of the rats (0.25, 0.47, 0.68, 0.30, and 0.89 for the control and YZG-331-H, YZG-330-H, YZG-331-L, and YZG-330-L, respectively) were interesting. This study provided a convenient and visual method to investigate in vivo molecular metabolic differences and provide insight towards a better understanding of the pharmacodynamic mechanisms of these sedative-hypnotic drug-candidates.

Pharmacological basis for sedative and hypnotic like effects of Pyrus pashia using in vivo experimental models.

Pyrus pashia has traditionally been used as a therapeutic agent including sedative. In this regard, hydroethanolic extract of Pyrus pashia (HEPP) was screened for phytochemical investigation, acute toxicity, and sedative-hypnotic activity to provide a scientific rationale to its ethno-medicinal uses. Mice were used in acute toxicity test; sedative potential was observed in open field test while thiopental-induced sleeping time and barbiturate-induced sleeping time tests were used for the assessment of hypnotic like effects of HEPP. Various phytochemical groups were detected in preliminary phytochemical tests. In acute toxicity study, the extract was found safe up to 1g/kg while the extract caused 50% death at 1500 mg/kg. In all animal models, the extract had shown sedative and hypnotic effects but the most significant effect observed at increased dose in comparison with standard diazepam-treated group. In open field test, the extract at doses of 200 and 400mg/kg, there is mild decrease in number of lines crossed by tested animals (mice) while significant reduction shown at 600mg/kg compared with diazepam-treated group at dose 0.5mg/kg. In phytochemical investigation HEPP subjected to different phytochemical tests. From the thoroughly study, it is revealed that these constituents mainly participating in sedation and hypnosis. The results of the present study showed significant sedative-hypnotic effects of the HEPP in mice and that the central benzodiazepine receptors are involved in the sedative-hypnotic effects of this plant.

The effects of dexmedetomidine on the bispectral index during cesarean section under general anesthesia with low-isoflurane anesthesia

Background Intraoperative awareness is a disturbing experience for all women undergoing general anesthesia for cesarean section; this may lead to posttraumatic stress which can last for many years. The bispectral index (BIS) is now widely used to evaluate the sedative hypnotic effect of anesthetic drugs. The effects of dexmedetomidine used with low concentration isoflurane on the BIS are investigated. Patients and methods After ethical approval, 40 parturients undergoing cesarean section received either normal saline, as a control group ( n =20), or 0.3 μg/kg/h intravenous dexmedetomidine 20 min before induction ( n =20) with anesthesia maintained using isoflurane 0.5 minimum alveolar concentration in 100% O 2 , fentanyl 1 μg/kg is given after fetal expulsion. Change in BIS, hemodynamic, uterine tone, Apgar score, sedative score, and pain score were recorded for all patients. Results Patients who received dexmedetomidine showed lower BIS values ( P P P P P P Conclusion The administration of dexmedetomidine 0.3 μg/kg/h is effective in maintaining a lower BIS with low-isoflurane anesthesia without adverse maternal or neonatal effects.

Hydroalcoholic Tarooneh Extract (Spathe of Phoenix Dactylifera) Increased Sedative-hypnotic Effects and Modulated Electroencephalography Brain Waves in Anesthetized Rats.

Background:Spathe of phoenix dactylifera is hard-covering envelope of date palm which is mentioned as a nerve relief in ancient medicine books. In this experiment, three extract doses used in sleeping time, sedative efficacy, and electroencephalography (EEG) protocol to show different aspects of extract effects on sleep.Materials and Methods:In three sleeping time, anesthesia time and EEG experiment protocols test group containing three extract doses (62.5, 125, and 250 mg/kg) were compared with saline control group, and in sleeping time experiment control group contained intact, midazolam, and saline group to detail more in behavioral Angel method.Results:Three extract doses increased sleeping time when compared with saline control group (P < 0.05). In evaluated sedative efficacy, two 125 and 250 mg/kg doses increased anesthesia and showed sedative effect (P < 0.05). In EEG experiment, dose 125 mg/kg increased delta waves and decreased high-frequency waves of alpha and beta. In addition, there were significant decreases in alpha waves of 62.5 and 250 mg/kg doses.Conclusion:Although all three doses increased sleeping time, dose 125 mg/kg is more efficient for deep and relaxing sleep and suits more for related researches.

Evaluation of Anticonvulsant Effect of Aqueous and Methanolic Extracts of Seven Inula Species.

In Iranian traditional medicine, Inula species have been used for the treatment of seizure. In this study we decided to investigate the anticonvulsant activity of seven species from this genus to find an effective remedy for seizure with less adverse effects compared to the available medicines. Aqueous and methanolic extracts of Inula britannica, Inula helenium, Inula viscidula, Inula oculus-christi, Inula aucheriana, Inula thapsoides, and Inula salicina were prepared and their antiepileptic activity was investigated by maximal electroshock (MES) and pentylentetrazole (PTZ) tests on Male NMRI Albino mice. Diazepam was used as positive control in both tests. In addition, two extracts with the best anticonvulsant activities were selected and their sedative and hypnotic effects were evaluated using open field and righting reflex tests, respectively. The effects of the both extracts on memory and motor coordination were also assessed by step-through passive avoidance and rotarod tests, respectively. Aqueous extract of Inula britannica and Inula viscidula showed the best activity in MES model and their ED50 (with 95% confidence interval) was 19.5 (7.9~48.5) mg/kg and 12.7(10.0~16.3) mg/kg, respectively. None of the extracts showed noticeable anticonvulsant effects in the PTZ model. The active extracts also showed sedative-hypnotic effects in righting reflex and open field tests. Furthermore, both extracts did not affect the memory and motor coordination in the experimental models. The anticonvulsant and sedative activities of the extracts were antagonized by flumazenil, indicating that benzodiazepine receptors are probably involved in the effects. This study indicates that Inula britannica and Inula viscidula are good candidates for further phytochemical and mechanistic studies in order to find anticonvulsant and sedative-hypnotic compounds with less adverse effect on memory and motor coordination.

Agarwood Essential Oil Ameliorates Restrain Stress-Induced Anxiety and Depression by Inhibiting HPA Axis Hyperactivity.

In our previous investigation, we found that agarwood essential oil (AEO) has a sedative-hypnotic effect. Sedative-hypnotic drugs usually have an anxiolytic effect, where concomitant anxiety and depression are a common comorbidity. Therefore, this study further investigated the anxiolytic and antidepressant effects of AEO using a series of animal behavior tests on a restraint stress-induced mice model. The elevated plus maze (EPM) test, the light dark exploration (LDE) test, and the open field (OF) test demonstrated that AEO has a significant anxiolytic effect. Simultaneously, the tail suspension (TS) test and the forced swimming (FS) test illuminated that AEO has an antidepressant effect with the immobility time decreased. Stress can cause cytokine and nitric oxide (NO) elevation, and further lead to hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. AEO was shown to dose-dependently inhibit the levels of cytokines, including interleukin 1α (IL-1α), IL-1β, and IL-6 in serum, significantly decrease the mRNA level of neural nitric oxide synthase (nNOS) in the cerebral cortex and hippocampus, and inhibit the nNOS protein level in the hippocampus. Concomitant measurements of the HPA axis upstream regulator corticotropin releasing factor (CRF) and its receptor CRFR found that AEO significantly decreases the gene expression of CRF, and significantly inhibits the gene transcription and protein expression of CRFR in the cerebral cortex and hippocampus. Additionally, AEO dose-dependently reduces the concentrations of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) downstream of the HPA axis, as measured by ELISA kits. These results together demonstrate that AEO exerts anxiolytic and antidepressant effects which are related to the inhibition of CRF and hyperactivity of the HPA axis.