Anxiolytic Component Research Articles

Exploring the anxiolytic mechanism of Fructus gardeniae based on metabolomics, network pharmacology, and molecular docking.

To explore the effect and anxiolytic mechanism of a natural remedy called Fructus gardeniae (FG). The elevated-plus maze (EPM) test was used to confirm the anxiolytic effect of FG. The potential and anxiolytic components, targets, and route processes of FG were investigated using the network pharmacology method in conjunction with metabolomics and molecular docking technologies. FG could greatly enhance the proportion of time and times of opening arms, according to the EPM data. As to the metabolomics findings, a total of 61 distinct metabolites were found, mainly involved in glycine, serine, and threonine metabolism as well as alanine, aspartate, and glutamate metabolism. The primary active ingredients of FG, nicotiflorin, jasminodiol, and crocetin, demonstrated substantial binding affinities with monoamine oxidase A (MAOA), monoamine oxidase A (ACHE), malate dehydrogenase 2 (MDH2), glutamate decarboxylase 2 (GAD2), glutamate decarboxylase 1 (GAD1), and nitric oxide synthase (NOS1), according to the findings of network pharmacology and molecular docking. FG exerts an anxiolytic action via targeting MAOA, ACHE, MDH2, GAD2, GAD1, and NOS1, and regulating the metabolism of glycine, serine, and threonine as well as alanine, aspartic acid, and glutamic acid.

Effects of RTI‐567 on the Neuropeptide S System

Anxiety and post‐traumatic stress have increasingly become more prominent disorders and options for treatment remain limited. One of the most prescribed therapeutics are benzodiazepines. Unfortunately, these anxiolytics have negative side effects and are not as effective in the long term. The recently discovered Neuropeptide S (NPS) system may lead to an alternative, potentially improved, line of therapeutics. This system consists of a known endogenous neuropeptide, Neuropeptide S and a G‐protein‐coupled receptor termed the Neuropeptide S receptor (NPSR). Activation of this receptor leads to an increase in intracellular calcium and a mobilization of cAMP. This is associated with behavioral phenotypes such as anxiolysis, enhanced memory consolidation, and hyperlocomotion. The NPSR is highly expressed in the amygdala linking the NPS system with fear and anxiety. Previously, as part of our ongoing drug discovery program, a biased agonist (RTI‐263) was identified that preferentially enhances the calcium signaling pathway over the cAMP pathway following NPSR binding. This biased agonist also reduced hyperlocomotion or arousal observed with NPS, while maintaining the anxiolytic component. In the present study we test another compound (RTI‐567) using classic anxiolytic, locomotor, and memory testing paradigms such as the light dark box, open field, and inhibitory avoidance. Our overall goal is to identify novel synthetic agonists with reduced side effects and improved long‐term efficacy.

Suivi thérapeutique pharmacologique de la cyamémazine : comment interpréter une concentration ? Une revue de la littérature

Cyamemazine is the most prescribed antipsychotic drug in France, often in combination with another antipsychotic, for its sedative and anxiolytic component. Providing to physicians serum concentrations of cyamemazine in different contexts (compliance checking, ineffectiveness, adverse effects, intoxication, modification of pharmacokinetic parameters…) requires to interpret them correctly. This article presents an update on how to interpret a concentration of cyamemazine, wich remains poorly documented. The anxiolysis occurs at steady-state serum trough concentrations of 4 to 5μg/L; the antipsychotic effect from 18-20μg/L. Cyamemazine is not a drug with a narrow therapeutic window and concentrations up to 400μg/L may be sought in cases of partial efficacy; concentrations of 1800μg/L might be fatal; lower concentrations might be fatal if association with high others concentrations of drugs.

Effect of Heteropterys aphrodisiaca on Anxiety and Male Exposure of Female Mice with Advanced Age.

Effect of Heteropterys aphrodisiaca (dog-node) on anxiety and function of adult female wistar mice. The project is an experiment with the use of H. aphrodisiac root extract, in order to observe the frequency of sexual exposure of females exposed to the extract, quantify the effect of the extract on the concentration of total testosterone and observe the anxiety levels of the animals exposed. Results will be measured with the laboratory testosterone test and LCE and CA tests. In preparation of the extract, the root was oven dried at 40°C and diluted in alcohol extract (100g of root for 1 liter of alcohol) and lyophilized. 40 adult female mice were enrolled, separated in control group (placebo) and treatment group (50 mg/kg/day) for 15, 30, 45 and 60 days. At each period, hormonal testosterone and anxiety levels by the Elevated-Cross Labyrinth (ECL) tests and Open Camp (CA) were measured in 10 animals that were later euthanized (SBNeC). The results showed an improvement in the decrease of anxiety, as shown in the variables of number of open arm entries, time on the same side of the field, less avoidance and leakage. However, it appears that the time of exposure to the extract does not result in increased benefit, with possible decline of effect after 45 days of use. With this performed experiment with the "no-de-cachorro" extract, it was possible to understand a little more how this root can act in relation to anxiety, as predicted by the pharmacology that validates the animal models; anxiolytic components decrease anxiety-related behaviors, as shown in the variables of entry numbers in the open arm, time on the same side of the field, less avoidance and escape. However, it seems that the time of exposure to the extract does not modify the performance in the tests, observing until an apparent exhaustion of the anxiolytic action, which evidences the need for more specific studies on the possible effects of the extract.

N-Phenylacetylglycyl-L-Proline Ethyl Ester Converts into Cyclo-L-Prolylglycine Showing a Similar Spectrum of Neuropsychotropic Activity

Previously designed cyclo-L-prolylglycine (CPG), a peptide prototype of piracetam, was discovered as an endogenous compound in rat brain and exhibited nootropic and anxiolytic properties. N-Phenylacetylglycyl-L-proline ethyl ester (GZK-111) was synthesized in the present work. It was established that GZK-111 converted to CPG and possessed nootropic, anxiolytic, and antihypoxic activities typical of CPG at doses of 0.1 – 1.5 mg/kg (i.p.). The effects of both GZK-111 and CPG were stereoselective with only the L-enantiomers being active. GZK-111 could be considered as a prodrug that enhanced cognitive functioning with an anxiolytic component.

Anxiolytic Potential of Methanol Extract from Ageratum conyzoides Linn Leaves

Objective: Ageratum conyzoides Linn. (Asteraceae) has been widely used in African traditional medicine for healing mental and infectious diseases. The present study was designed to scientifically validate the traditional claim of A. conzyoides as anti-anxiety drug and to identify the compound responsible for the anxiolytic effects of A. conzyoides. Method: The methanol extract of A. conzyoides was prepared by soxhlet apparatus. The methanol extract was fractionated into ethylacetate and butanol fractions by liquid-liquid partitioning method. Methanol extract (100 and 200 mg/kg; p.o.) and its prepared fractions (25 and 50 mg/kg; p.o.) were evaluated for anxiolytic activity in mice by using elevated plus maze (EPM) model. Thin layer chromatography studies were performed to identify the possible anxiolytic component. Results: Methanol extract at both doses showed significant, when compared to vehicle control group, increase in time spent and number of entries in open arms of EPM confirming the anti-anxiety effects of A. conzyoides. Liquid-liquid partitioning of methanol extract gave two fractions (ethylacetate and butanol) which were administrated at 25 and 50 mg/kg doses to mice in EPM, respectively. Results showed that ethylacetate fraction was responsible for anxiolytic effects of methanol extract of A. conzyoides. The TLC studies were carried out for ethylacetate fraction and Quercetin was identified by comparing Rf values with the standard (Quercetin). Conclusion: The present investigation revealed that the extract has significant anxiolytic effect. The flavonoid quercetin may be responsible for the observed anxiolytic effects of A. conyzoides.

Kava - Its Resurgence, Quality Control, Anxiolytic Activity, and Hepatotoxic Risk, a Natural Medicine with Future Promise and Challenges

Consumed as a daily beverage by South Pacific islanders for centuries, traditional kava is prepared as an aqueous extract of the roots of Piper methysticum. Other than its traditional use, kava had previously been employed clinically to treat mild to moderate anxiety and was widely available as a dietary supplement for such use. Reports of rare hepatotoxicity linked to use of unspecified kava products led to its removal from the European market. Subsequently, in 2002, the US FDA issued a warning regarding potential hepatotoxicity and although kava was not banned, safety and liability concerns led most manufacturers to abandon commercialization of kava as a dietary supplement. Surprisingly, kava is experiencing a dramatic resurgence in popularity globally and increased human exposure is evident and inevitable. Our team conducted an analysis of kava exportation from Vanuatu, Fiji, and Tonga. Between 2009 and 2011 kava exports from these countries increased each year and were noted to be 727, 804 and 1089 tons respectively, a significant portion being to the USA, demonstrating large and increasing popularity among certain populations. Although it is commonly believed that kava use is associated with liver injury, a cause and effect relationship as well as mechanism of action for such injury remains ill defined. Furthermore, it is unknown which components of kava may be responsible for injury and whether or not the extraction process and resulting chemical characteristics may have played a role in previously reported adverse events. Considering that human use is continuing and increasing, there may or may not be a significant emerging public health issue. Therefore, renewed interest in researching potential cause and effect relationships between kava use, its clinical utility and liver injury is warranted. Kava's anxiolytic activity is attributed to kavalactone-based chemicals yet there have been no animal or human studies to confirm the anxiolytic component(s). From a safety perspective, many factors influence the composition of kava products, and various hypotheses have been proposed for its hepatotoxic risk but again none has validated a cause and effect relationship or mechanism of action. Pending the outcome of more definitive toxicity investigations, additional studies to validate the active components and mechanism of action for its anxiolytic effects are also warranted and may lead to successful reintroduction of safer commercial forms of kava with substantial potential for beneficial clinical use. Our team proposes new approaches to study this issue and will present suggested appropriate models for further investigation.

Anxiety- rather than depression-like behavior is associated with adult neurogenesis in a female mouse model of higher trait anxiety- and comorbid depression-like behavior

Adult neurogenesis has been implicated in affective disorders and the action of antidepressants (ADs) although the functional significance of this association is still unclear. The use of animal models closely mimicking human comorbid affective and anxiety disorders seen in the majority of patients should provide relevant novel information. Here, we used a unique genetic mouse model displaying higher trait anxiety (HAB) and comorbid depression-like behavior. We demonstrate that HABs have a lower rate of hippocampal neurogenesis and impaired functional integration of newly born neurons as compared with their normal anxiety/depression-like behavior (NAB) controls. In HABs, chronic treatment with the AD fluoxetine alleviated their higher depression-like behavior and protected them from relapse for 3 but not 7 weeks after discontinuation of the treatment without affecting neurogenesis. Similar to what has been observed in depressed patients, fluoxetine treatment induced anxiogenic-like effects during the early treatment phase in NABs along with a reduction in neurogenesis. On the other hand, treatment with AD drugs with a particularly strong anxiolytic component, namely the neurokinin-1-receptor-antagonist L-822 429 or tianeptine, increased the reduced rate of neurogenesis in HABs up to NAB levels. In addition, challenge-induced hypoactivation of dentate gyrus (DG) neurons in HABs was normalized by all three drugs. Overall, these data suggest that AD-like effects in a psychopathological mouse model are commonly associated with modulation of DG hypoactivity but not neurogenesis, suggesting normalization of hippocampal hypoactivity as a neurobiological marker indicating successful remission. Finally, rather than to higher depression-related behavior, neurogenesis seems to be linked to pathological anxiety.

The Effect of Citalopram on Midbrain CRF Receptors 1 and 2 in a Primate Model of Stress-Induced Amenorrhea

We have demonstrated marked differences in the neurobiology of the serotonin system between stress-sensitive (SS) and stress-resilient (SR) cynomolgus macaques characterized in a model of stress-induced amenorrhea, also called functional hypothalamic amenorrhea (FHA). Dysfunction of the serotonin system in SS monkeys suggested that administration of a selective serotonin reuptake inhibitor (SSRI) might correct FHA. This study examines the effect of escitalopram (CIT) administration to SS and SR monkeys on corticotrophin-releasing factor (CRF) receptor 1 (CRF-R1) and CRF receptor 2 (CRF-R2) gene expression in the serotonin cell body region of the midbrain dorsal raphe. CRF-R1 was not significantly different between groups. There was a significant effect of treatment and a significant interaction between treatment and stress sensitivity on the average CRF-R2-positive pixel area (P < .004 and P < .006, respectively) and on the average number of CRF-R2-positive cells (P < .023 and P < .025, respectively). CIT significantly increased CRF-R2-positive pixel area and cell number in the SS group (pixel area P < .001; cell number P < .01; Bonferoni) but not in the SR group. In summary, CIT administration tended to decrease CRF-R1, but the small animal number precluded significance. CIT administration significantly increased CRF-R2 only in SS animals. These data suggest that the administration of CIT reduces anxiogenic components and increases anxiolytic components of the CRF system in the midbrain serotonin network, which in turn leads to improved ovarian function. Moreover, these data raise the possibility that SSRIs may be effective in the treatment of stress-induced infertility.

Synthesis and pharmacological activity of the main metabolite of afobazole and its analogs

The methods and conditions for the synthesis of the main metabolite of the selective anxiolytic afobazole, 2-[2-(3-oxomorpholin-4-yl)ethylthio]-5-ethoxybenzimidazole, and its analogs are developed. It is shown that the main metabolite demonstrates an anxiolytic effect in a dose range similar to that of afobazole. It is found that the psychopharmacological profile of the other synthesized compounds (analogs) is characterized by a less pronounced anxiolytic component.

Identification of anxiolytic ingredients in ginseng root using the elevated plus-maze test in mice

Ginseng root has been widely used for the management of anxiety and emotional instability, but there is little experimental evidence supporting these clinical applications. We pharmacologically identified the anxiolytic components in ginseng root, using the elevated plus-maze test. Male ICR albino mice and the following drugs were used: diazepam (0.5, 1 and 1.5 mg/kg, p.o.); red ginseng powder (300, 600 and 1200 mg/kg, p.o.); crude saponin and non-saponin ginseng fractions (50, 100 and 200 mg/kg, i.p., for each preparation); and pure ginsenoside Rb 1, Rg 1, and Ro (2.5, 5 and 10 mg/kg, i.p., for each preparation). Ginseng powder and crude saponin ginseng fraction significantly increased the frequency and duration of open arm entries. Among the three types of pure ginsenoside, only ginsenoside Rb 1 significantly increased both the frequency and duration of open arm entries. Our results clearly indicate that ginsenoside Rb 1 is one of the active anxiolytic components of ginseng root.

Identification of magnolol and honokiol as anxiolytic agents in extracts of saiboku-to, an oriental herbal medicine.

The principal active anxiolytic components in Saiboku-to, an Oriental herbal medicine, have been isolated and identified as magnolol (5,5'-di-2-propenyl-1,1'-biphenyl-2,2'-diol) and honokiol (3',5-di-2-propenyl-1,1'-biphenyl-2,4'-diol). Evaluation by means of an elevated plus-maze test showed that honokiol was at least 5000 times more potent than Saiboku-to when mice were treated orally for 7 days.

Pharmacologically active components of a Peruvian medicinal plant, huanarpo (Jatropha cilliata).

From Jatropha cilliata M. Arg., a Peruvian medicinal plant, isoorientin and orientin were isolated as anxiolytic components by using the isolation guide of anti-conflict effect in mice. Several related flavonoids were also tested for this effect. Another bioassay-guided isolation using the acetic acid-induced writhing method gave a coumarin compound, fraxetin, as an analgesic principle.

5-HT 1A receptor ligands in animal models of anxiety, impulsivity and depression: Multiple mechanisms of action?

1. Preclinical and clinical studies suggest that 5-HT 1A receptor agonists are a new class of mixed axiolytics/antidepressants with, possibly, impulsivity reducing properties. 2. The anxiolytic effects of 5-HT 1A receptor agonists result predominantly from an interaction with presynaptic 5-HT 1A receptors (resulting in a decrease of serotonergic transmission), whereas the antidepressive and, possibly, the impulse control enhancing effects, result predominantly from an interaction with postsynaptic 5-HT 1A receptors. 3. These proposed mechanism(s) of action fit well with the generally held view that anxiety is the result of a hypersensitive 5-HT system; whereas impulsivity and depression is the result of a hyposensitive 5-HT system. 4. However, it appears very likely that activation of pre- and postsynaptic 5-HT 1A receptors is additionally involved in the antidepressive and impulse control enhancing effects, on the one hand, and in the anxiolytic effects of these compounds, on the other hand. 5. These latter, seemingly paradoxical, findings can be explained by assuming that (1) the presynaptic mechanism reflects an anxiolytic component in the animal models of impulsivity and depression, (2) antagonism of postsynaptic 5-HT 1A receptors by these compounds contributes to their anxiolytic effects, (3) postsynaptic 5-HT 1Aand 5-HT 2 receptors have functionally opposing effects or, alternatively, that (4) downregulation of postsynaptic 5-HT 2 receptors contributes to the therapeutic effects of these compounds.

Treatment of childhood and adolescent depression with mianserin.

The efficacy of mianserin in treating adult depression is now well established. Since there are no publications concerning the use of mianserin in children, the authors set up an open pilot study of 110 depressed children and adolescents aged 8-19 years. The average dose of mianserin was 1 mg/kg/day. Efficacy of treatment was noticeable by the end of the first week and was maintained throughout the 60 day study period. Evaluation was based on both clinical observations and changes in scores obtained from 80 subjects. Side-effects were minimal leading to temporary withdrawal of treatment in only seven cases. The profile of mianserin in children and adolescents is similar to that of adults. It is an antidepressant with an anxiolytic component, and has a regulating effect on sleep. In view of its efficacy, compliance, and the very low incidence of side-effects, mianserin appears to be a useful treatment for depression in children and adolescents. The results of this open study justify the development of further controlled studies.

Some aspects of the psychopharmacological activity of maprotiline (Ludiomil): effects of single and repeated treatments.

Three different aspects of the psychopharmacological activity of the antidepressant maprotiline were investigated: its influence on serotoninergic functions the effects produced by chronic treatment its central nervous depressant and anxiolytic properties. Study of the effects of maprotiline on 5-HTP-induced head-twitch in mice pre-treated with pargyline or on hyperpyrexia in rats provided no evidence that the drug interferes with serotonin-mediated functions in the central nervous system even after quite high doses. These findings corroborate the results of extensive neurobiochemical investigations, which failed to demonstrate any influence of maprotiline on the metabolism of serotonin. Chronic studies showed that classical effects of maprotiline such as antagonism against reserpine-induced ptosis or tetrabenazine-induced catalepsy do not change in their intensity after daily administration of the drugs in a dose of 30 mg/kg p.o.for 11 days. A new component of the action of the compound, not detectable after one single dose, seems to appear, however, after repeated treatment (8 days). This effect is manifested in the restoration of conditioned avoidance behaviour after its suppression by pre-treatment with reserpine. The same effect is produced by imipramine. It is suggested that this restorative effect may be due to an additional activation of the dopaminergic nervous system and may have a bearing on the appearance of clinical antidepressant effects. Maprotiline was found to potentiate central nervous depressant effects of drugs like chlorpromazine, phenobarbitone and propranolol. This affords further confirmation that, in addition to its antidepressant qualities, it possesses sedative actions. An anxiolytic component was also demonstrated in rats in which maprotiline suppressed the conditioned, fear-induced rise in body-temperature.