Food-derived protein hydrolysates and peptides:anxiolytic and antidepressant activities,characteristics,and mechanisms

Globally,the prevalence of anxiety and depression has reached epidemic proportions.Food-derived protein hydrolysates and peptides delivered through dietary supplementation can avoid the negative risks associated with traditional pharmaceuticals while delivering superior anxiolytic and antidepressant effects.This review summarizes current research on food-derived anxiolytic and antidepressant protein hydrolysates and peptides,and subsequently analyses their physicochemical characteristics and elaborates on their mechanisms.The aim of this work is to contribute to the in-depth study and provide a theoretical foundation for the development of related products to better serve patients with anxiety and depression.

Anticancer,Anti-inflammatory,Analgesic,and Anxiolytic Effects of Koumine and Their Molecular Mechanisms

Koumine is an indole alkaloid monomer extracted from the Chinese herb Gelsemium elegans,which has a variety of pharmacological effects.This paper provides a comprehensive summary of the pharmacological effects and molecular mechanisms of koumine,with a particular emphasis on its mechanisms of action in the context of anticancer,anti-inflammatory,analgesic,and anxiolytic properties.The aim is to provide a theoretical foundation for further research and the application of koumine in clinical practice.

Comprehensive Assessment of Anxiolytic Properties in 4-HPAA Derivatives: Bridging in Vivo Validation and Molecular Docking Analyses

Anxiety is a significant mental health issue that substantially affects an individual’s quality of life. Feelings of uneasiness, irritability, and sleep disturbances characterize it. 4-Hydroxyphenyl acetic acid (4-HPAA) is identified in brain cells as a physiological byproduct of tyramine. This study hypothesizes that 4-HPAA may regulate anxiety due to its anxiolytic properties, acting as a modulator of the GABAergic system, which plays a crucial role in the pathophysiology of anxiety disorders. Our study aims to enhance the anxiolytic effects of 4-HPAA through chemical modification to improve its pharmacokinetic properties. Three derivatives, namely Isopropyl-4-hydroxy-[phenyl] acetate (IHPA), Isopropyl-4-hydroxy-[phenyl] acetate (MPAA), and 4-methoxyphenyl acetate (MPHA), have been synthesized from 4-HPAA. This assessment will use well-established animal models, specifically the Elevated Plus-Maze (EPM) and Zero Maze (EZM) tests, selected for their validity in replicating anxiety-like symptoms in animals. Chronic caffeine administration via drinking water (0.3 g/l for 14 days) was employed to induce an anxiety state for testing purposes. IHPA and MPAA demonstrated significant anxiolyticactivity when tested in the EPM and EZM experiments. Molecular docking simulations using AutoDock Vina indicated that 4-HPAA derivatives had docking scores ranging from −5.8 to −4.8 kcal/mol, compared to the standard anxiolytic medication Diazepam, which scored −7.1 kcal/mol. These scores suggest a potential for 4-HPAA derivatives to interact effectively with the Gamma-aminobutyric acid (GABA_A) receptor. In conclusion, our in vivo and in silico analyses indicate a promising anxiolytic potential for 4-HPAA derivatives.

Anxiolytic potential of ursolic acid derivative-a stearoyl glucoside isolated from Lantana camara L.(verbanaceae)

Objective:To investigate the anxiolytic activity of newly isolated compound by our lab called ursolic acid stearoyl glucoside(UASG) from the leaves of Lantana camam(L camam).Methods: Column chromatography was used to isolate UASG.Anxiolytic potential was experimentally proved and demonstrated through Elevated plus-maze,Open field and light and dark test. Results:The UASG showed marked increased in time spent(%) and number of frequent movements made by animals in open arm of elevated plus-maze apparatus.In light and dark model,UASG produced marked increase in time spent by animal,number of crossing and reduced duration of immobility in light box.Conclusions:UASG showed significant increase in number of rearing,assisted rearing and number of square crossed in open field established test model.UASG showed its anxiolytic effect in dose dependent manner.

Anxiolytic and free radical scavenging potential of Chinese celery(Apium graveolens) extract in mice

Objective: To elucidate the anxiolytic and free radical scavenging effect of methanolic extract of Apium graveolens(A. graveolens) in adult C57BL/6 mice.Methods: Sixty male mice were divided into 6 groups: control, vehicle, positive control and A. graveolens(125, 250 and 500 mg/kg). Different behavioral models of elevated plus maze, open field, light/dark, hole-board and pentobarbital-induced sleep were used to assess anxiety-like behavior. Biochemical parameters including monoamine oxidase-A(MAO-A) activity, lipid peroxidation, % inhibition of superoxide anion and glutathione peroxidase activity were measured. Histologic studies were also examined.Results: Mice receiving various doses of A. graveolens(125, 250 and 500 mg/kg)showed an alleviation of anxiety-like behavior as evidenced by the battery of behavioral tests. Likewise, A. graveolens treatment was found to significantly decrease MAO-A activity, lipid peroxidation as well as cause a significant increase of % inhibition of superoxide anion and glutathione peroxidase activity in both cortex and striatum. The total number of survival neurons found in the frontal cortex and striatum was significantly higher than that of the vehicle-treated group.Conclusions: Taken together, we showed that A. graveolens improve the behavioral changes which might be related to the inhibition of free radicals and modulation of MAOA activity resulting in an increased number of survival neurons. Our findings suggest the therapeutic potential of A. graveolens in the treatment of anxiety.

Identification of Anxiolytic Potential of Niranthin:In-vivo and Computational Investigations

Anxiety is an unpleasant state,which can critically decrease the quality of life is often accompanied by nervous behaviour and rumination.Niranthin is a lignan isolated from various Phyllanthus sources.The literature survey on niranthin highlights wide ranges of the therapeutic potentials.In a present study,based on our previous investigations,we evaluated pure,isolated and characterized niranthin as an anxiolytic agent.The niranthin[6-[(2R,3R)-3-[(3,4-dimethoxyphenyl)methyl]-4-methoxy-2-(methoxymethyl)butyl]-4-methoxy-1,3-benzodioxole]was purchased from commercial source and further subjected for assessment of its anxiolytic potentials using popular animal models including Elevated plus-maze model/test(EPM)and Light&Dark Exploration test(L&D).GABA-A receptor mediation was evaluated by pretreating the mice with the GABA-A receptor antagonist Flumazenil before the EPM task.Molecular docking simulation studies(pdb id:4COF)carried out by Vlife QSAR software showed that niranthin(docking score:−62.1714 kcal/mol)have shown comparatively best docking score compared to the standard drug Diazepam(docking score:−63.1568 kcal/mol).To conclude,Niranthin has probable potential in the management of anxiety disorder.Our in-silico and in-vivo analysis(indirectly)indicated the plausible role of GABA mediation for anxiolytic activity.Although,these studies are preliminary,future in depth experimental explorations will be required to use Niranthin as anti-anxiety drug in near future.

Evaluation of Anxiolytic and Sedative-Like Activities of Methanolic Extract of <i>Euphorbia hirta</i>Leaves in Mice

In indigenous or folk medicine, Euphorbia hirta is a very popular herb and used as a palliative to treat various ailments including intestinal parasites, diarrhoea, vomiting, amoebic dysentery, asthma, bronchitis, emphysema, coughs, kidney stones, menstrual problems etc. The objective of this study is to evaluate the anxiolytic and sedative-like effects of the methanol extract from the leaves of Euphorbia hirta (Euphorbiaceae). Methanolic extract of Euphorbia hirta was evaluated for its CNS depression effect using mice behavioral models such as, elevated plus maze and hole board test for its anxiolytic potential where hole cross and pentobarbital-induced sleeping time tests were performed for its sedative properties, respectively. The test group received three different doses of the MEHL (100 mg/kg, 200 mg/kg and 300 mg/kg) orally. The positive control group received diazepam (1 mg/kg) orally where the negative control group received distilled water (10 ml/kg) orally. In elevated plus maze test, the extract exhibited significant (p d the number of open arm entry and time spent in open arm by mice compared to control group. In addition, the number of head dips and hole crosses significantly (p < 0.05) decreased by mice in hole board and hole cross tests respectively, compared to control group. Moreover, mice treated with MEHL significantly decrease the onset of sleep and increase the duration of sleep in pentobarbital-induced sleeping time test in mice compared to control group. The data obtained from the present study clearly demonstrate that the methanolic extract of Euphorbia hirta has potential anxiolytic and sedative-like activity in the animal behavioral models. And the findings represent a rational explanation for its use in traditional medicine for the management of neurological disorder.

Anxiolytic Effects of the Methanolic Extract of <i>Bacopa monniera</i>in Mice

Bacopa monniera Linn. or Brahmi, a plant in the family Scrophulariaceae, is used as a traditional medicine for memory improvement, dementia like anxiety, depression, epilepsy etc. for a long time in Bangladesh. This study evaluated the anxiolytic effects of the methanolic extract of B. monniera (MEBM) in animal models of anxiety. For the further tests and phytochemical screening, the whole plant of B. monniera extracted following maceration method. The extract was evaluated for anxiolytic activity using light/dark box, elevated plus maze, marble burying and rota rod tests in mice at the doses of 50, 100, and 200 mg/kg body weight. Diazepam (1.0 mg/kg), an anxiolytic drug used as standard drug. MEBM showed a strong and dose-dependent anxiolytic effects in animal models of anxiety. MEBM significantly increased the time spent in the light compartment, the latency time, and the entries of open arms in light/dark and elevated plus maze tests. In addition, MEBM also significantly decreased the number of buried marbles in marble burying test and increased the time of performance in rota rod test (p < 0.05). These were the major findings of this study. Therefore, our results reported that MEBM possesses anxiolytic effects in animal models of anxiety that support the traditional use of this plant as a potent agent to combat anxiety.

<i>In Vivo</i>Sedative and Anxiolytic Activities of <i>Thunbergia erecta</i>(Acanthaceae) Leaves Activate Gamma-Aminobutyric Acid (GABA) Mediated Hyperpolarization in Swiss Albino Mice

Background: Thunbergia erecta (Acanthaceae) is the most abundant medicinal plant in different parts of Bangladesh where it is known as “nilghonta”. It has been used as traditional medicine for insomnia, depression and anxiety management. However, no scientific evidence of T. erecta belonging to neuropharmacological activity has been reported. The aim of present study was to investigate in vivo sedative and anxiolytic activities of methanol extract from the leaves of T. erecta in Swiss Albino mice. Methods: Sedative activity of METE was investigated using open field, hole cross and thiopental sodium-induced sleeping time test model whereas anxiolytic activity was screened by elevated-plus maze, light-dark box, hole-board and marble-burying test method in mice at 200 and 400 mg/kg doses. The acute toxicity study and phytochemical analysis of METE also carried out. Diazepam used as the positive control for the following behavioral pharmacology test. Results: METE exhibited significant (p Conclusion: The experimental result indicates T. erecta contains phytoconstituents that possess sedative and anxiolytic activity which traditionally used in insomnia, depression and anxiety management.

The potential of Chinese herbal medicines in treating anxiety disorders

In recent years,there has not been much progress in developing anxiolytic drugs.Amongst the barriers are the lack of clarity on the pathogenesis of anxiety disorders,low product conversion rates for developing drugs targeting the receptors,and species variability.Some scientists have focused on natural medicines,especially herbal medicines in traditional Chinese medicine.New drugs with excellent anxiolytic activity are hoped to be found in herbal medicines with anxiolytic effects.This mini-review summarised three Chinese herbal medicines with anxiolytic effects and anxiolytic herbal formulas used in the traditional Chinese medicine clinic.Several key issues that block the development of new anxiolytic drugs are also discussed.We hope to provide some ideas for researching and developing new anxiolytic drugs and studying anxiolytic components in traditional Chinese medicine.

Anxiolytic Effect of Increased NREM Sleep after Acute Social Defeat Stress in Mice

Social defeat stress(SDS)plays a major role in the pathogenesis of psychiatric disorders like anxiety and depression.Sleep is generally considered to involve recovery of the brain from prior experience during wakefulness and is altered after acute SDS.However,the effect of acute SDS on sleep/wake behavior in mice varies between studies.In addition,whether sleep changes in response to stress contribute to anxiety is not well established.Here,we first investigated the effects of acute SDS on sleep/wake states in the active period in mice.Our results showed that total sleep time(time in rapid eyemovement[REM]and non-REM[NREM]sleep)increased in the active period after acute SDS.NREM sleep increased mainly during the first 3 h after SDS,while REM sleep increased at a later time.Then,we demonstrated that the increased NREM sleep had an anxiolytic benefit in acute SDS.Mice deprived of sleep for 1 h or 3 h after acute SDS remained in a highly anxious state,while in mice with ad libitum sleep the anxiety rapidly faded away.Altogether,our findings suggest an anxiolytic effect of NREM sleep,and indicate a potential therapeutic strategy for anxiety.

Evaluation of anxiolytic and hypoglycemic activity of methanolic extract of Ixora cuneifolia in an animal model

Objective: To investigate anxiolytic and hypoglycemic activity of Ixora cuneifolia (Family:Rubiaceae) in an experimental animal model. Methods: Anxiolytic test was performed by elevated plus maze (EPM) and hole-board method. Hypoglycemic activity was measured in glucose-loaded Swiss albino mice by glucose tolerance test. Results: The methanol extract of Ixora cuneifolia exhibited dose-dependent and statistically significant (P < 0.05) anxiolytic activity at doses of 200 and 400 mg/kg. Reduction of glucose level was observed with the highest dose 400 mg/kg of the extract in glucose tolerance test. Conclusions: The better anxiolytic and hypoglycemic activities in the present study could be due to the presence of different chemical constituents like alkaloids, flavonoids, saponin, phenols and tannins in this methanolic extract.

Evaluation of the analgesic,sedative-anxiolytic,cytotoxic and thrombolytic potentials of the different extracts of Kalanchoe pinnata leaves

Objective:To evaluate the analgesic,neuropharmacological,cytotoxic and thrombolytic potentials of the aqueous,ethanol and ethyl acetate extracts of Kalanchoe pinnata leaves.Methods:At the dose of 400 mg/kg body weight,the analgesic activity of the extracts were evaluated by the acetic acid-induced writhing and formalin-induced persistent pain tests while neuropharmacological activity was evaluated by the open field,hole cross and elevated plus maze tests.The cytotoxic potential was observed by brine shrimp lethality bioassay and the thrombolytic potential was investigated by clot lysis test.Results:The aqueous extract significantly suppressed the number of writhing(96.78%)as well as the formalin-induced persistent pain on the early phase(46.92%)and on the late phase(40.98%).Again in case of hole cross and open field tests,the locomotor activity was decreased significantly(P<0.001)mostly by the ethyl acetate extract.Furthermore,the sedative-anxiolytic activity was supported by the increased percent(P<0.01)of frequency into the open arm on elevated plus maze test.Besides,the extracts showed moderate lethality and thrombolytic activity.Conclusions:The findings showed that activities are comparable to the standards and in some cases are stronger than the standards.Therefore,based on the results,it is evident that it has great analgesic and sedative-anxiolytic activity with moderate cytotoxic and thrombolytic potential.

Antidepressant,anxiolytic and anti-nociceptive activities of ethanol extract of Steudnera colocasiifolia K.Koch leaves in mice model

Objective:To estimate the antidepressant,anxiolytic and antinociceptive activities of ethanol extract of Steudnera colocasiifolia K.Koch(S.colocasiifolia)leaves.Methods:Swiss albino mice treated with 1%Tween solution,standard drugs and ethanol extract of S.colocasiifolia,respectively,were subjected to the neurological and antinociceptive investigations.The tail suspension test and forced swimming test were used for testing antidepressant activity,where the parameter is the measurement of immobility time.Anxiolytic activity was evaluated by hole board model.Anti-nociceptive potential of the extract was also screened for centrally acting analgesic activity by using formalin induced licking response model and acetic acid induced writhing test was used for testing peripheral analgesic action.Results:Ethanol extract of S.colocasiifolia significantly decreased the period of immobility in both tested models(tail suspension and forced swimming models)of antidepressant activity.In the hole board model,there was a dose dependant(at 100 and 200 mg/kg)and a significant increase in the number of head dipping by comparing with control(1%Tween solution)(P<0.05 and P<0.001).In formalin induced licking model,a significant inhibition of pain compared to standard diclofenac sodium was observed(P<0.05 and P<0.001).In acetic acid induced test,there was a significant reduction of writhing response and pain in mice treated with leaves extract of S.colocasiifolia at 200 mg/kg body weight(P<0.05 and P<0.001).Conclusions:The results proofed the prospective antidepressant,anxiolytic and antinociceptive activities of ethanol extract of S.colocasiifolia leaves.

Pharmacological Action and Molecular Mechanism of Formononetin

Formononetin is an isoflavone phytoestrogen mainly existing in leguminous plants such as Trifolium pretense,Spatholobus suberectus,etc.Studies have proved that formononetin has good anti-inflammatory,antitumor,antioxidant,antidepressant,anxiolytic and other pharmacological effects.This paper summarizes the pharmacological action and molecular mechanism of formononetin,in order to provide a theoretical basis for the development and clinical application of formononetin.

Central nervous system activity of Illicium verum fruit extracts

Objective:To research the acute toxicity of Illicium verum(I.verum)fruit extracts and its action on central nervous system.Methods:The TLC and HPTLC techniques were used as fingerprints to determine the chemical components present in I.verum.Male albino rats and mice were utilized for study.The powdered material was successively extracted with n-hexane,ethyl acetate and methanol using a Soxhlet extractor.Acute toxicity studies were performed as per OECD guidelines.The CNS activity was evaluated on parameters of general behavior,sleeping pattern,locomotor activity,anxicty and myocoordination activity.The animals were trained for seven days prior to experiments and the divided into five groups with six animals in each.The drug was administered by intraperitoneal route according to body weight.The dosing was done as prescribed in each protocol.Results:Toxicity studies reported 2 000 mg/kg as toxicological dose and 1/10 of the same dose was taken as therapeutic dose Intraperitoneal injection of all extracts at dose of 200 mg prolonged phenobarbitone induced sleeping time,produced alteration in general behavior pattern,reduced locomotor activity and produced anxiolytic effects but the extracts do not significantly alter muscles coordination activity.The three extracts of I.verum at the dose of 200 mg,methanol extract was found to produce more prominent effects,then hexane and ethylacetate extracts.Conclusions:The observation suggested that the extracts of I. verum possess potent CNS depressant action and anxiolytic effect without interfering with motor coordination.

Neuropharmacological evaluation of methanolic extract of Costus speciosus Linn. rhizome in Swiss albino mice

Objective: To evaluate the neuropharmacological properties of Costus speciosus(C. speciosus) rhizome using different experimental mouse models. Methods: The anxiolytic effect was investigated by hole-board test, elevated plus maze and light/dark test, while central nervous system(CNS) depressant effect was evaluated by thiopental sodium-induced sleep test. Finally, antidepressant effect was evaluated by forced swimming test and tail suspension test. Results: In both elevated plus maze and hole board test, 400 mg/kg C. speciosus showed more significant CNS depressant effect than 1 mg/kg diazepam. Both 200 mg/kg and 400 mg/kg C. speciosus extract produced a significant dose-dependent decrease in onset of sleep. In forced swimming test, C. speciosus rhizome showed a decrease in duration of immobility in a dose-dependent manner. Imipramine(10 mg/kg) and C. speciosus extract at 400 mg/kg dose exhibited a significant reduction in duration of immobility in tail suspension test which provided additional evidence of antidepressant effect of C. speciosus rhizome. Conclusions: Our study indicates that C. speciosus rhizome possesses CNS depressant, anxiolytic and antidepressant-like activities. Further studies are warranted determine the exact phytoconstituents and mechanism of action responsible for the neuropharmacological effect.

Neuropsychopharmacological profile of Astragalus membranaceous var.mongholicus

Objective:To clarify the neuropharmacological profile of the Mongolian vetch,Astragalus mongholicus(Astragalus membranaceous var.mongholicus;synonym:A.mongholicus),extracts were evaluated for behavioral effects in rats and mice.Methods:An aqueous extract of A.mongholicus was made by boiling roots from freshlycollected plants in 2.5 volumes(w/v)of water for 60 minutes.An ethanol extract was made by incubating in 70%ethanol for 5 days at 25
C.Effects of the aqueous extracts were evaluated in a forced swimming assessment of antidepressant effects,a hole-board test of exploratory behavior,an analysis of inhibition of aggression following electrical stimulation and influences on amnesia resulting from electroshock.Furthermore,effects of ethanol extracts of A.mongholicus were assessed on L-tryptophan induced twitches(indicating serotonin-mediated effects)and on hypothermia induced by apomorphine(indicating dopamine-mediated interactions)in mice.Results:Per os(PO)administration of the aqueous decoction of the vetch to rats increased the response in a forced swimming test as reflected in wheel rotations.However,the decoction had no significant effect on the exploratory behavior of rats in the hole-board test.Acute PO administration of the aqueous extract of A.mongholicus decreased the threshold for aggressive behavior and this effect persisted with subchronic administration.Chronic administration of the plant extract suppressed aggression of rats.An ethanol extract of A.mongholicus showed an antiserotoninergic action and had a significant influence on the hypothermia induced by apomorphine.Conclusion:A.mongholicus has a variety of potent psychotropic actions,suggesting influences on diverse neurotransmitter systems.

GABAA Receptor Modulation by Compounds Isolated from <i>Salvia triloba</i>L.

Salvia triloba, traditionally known as Greek sage, has been used to enhance memory, as a sedative and to treat headaches. Pharmacological evaluation of purified extracts and isolated compounds of S. triloba were carried out on functional assays using two-electrode voltage clamp methods on recombinant GABA receptors expressed in Xenopus laevis oocytes. Bio-assay guided fractionation led to seven compounds being isolated from S. triloba: ursolic acid, carnosol, oleanolic acid, salvigenin, rosmanol, cirsimaritin and hispidulin. The purified extracts of S. triloba inhibited 54% of the current produced by 300 μM GABA at α1β2γ2L GABAA receptors. Ursolic acid, carnosol, oleanolic acid and rosmanol also acted as negative allosteric modulators. The flavonoids salvigenin, cirsimaritin and hispidulin acted as positive modulators when applied in the presence of low concentrations of GABA but in the presence of high concentrations of GABA acted as negative modulators, demonstrating a biphasic action. These results are consistent with the concept that Salvia triloba may have cognition enhancing properties. In most cases these activities are likely to be occurring via different modulatory sites on GABAA receptor complexes. It may be that the combination of these activities permits cognition enhancement whilst offering protection from convulsant activity.

Investigation of in vivo neuropharmacological effect of Alpinia nigra leaf extract

Objective:To analyze in vivo neuro-pharmacological effects of Alpinia nigra as anxiety is a particular form of behavioral inhibition that occurs in response to novel environmental events.Methods:In present study,the extract of Alpinia nigra was evaluated for its central nervous system depressant effect using mice behavioral models,such as hole cross,open field and thiopental sodium induced sleeping time tests for its sedative properties and an elevated plusmaze test for its anxiolytic potential,respectively.Results:In anxiolytic study,the extract displayed increased percentage of entry into open arm ut the dose of 400 and 200 mg/kg.The extract produced a significant(P<0.01) increase in sleeping duration and reduction of onset of sleep compared to sodium thiopental at both doses(200 and400 mg/kg).The extract t.200 and 400 mg/kg) also showed a dose-dependent suppression of motor activity and exploratory activity of the mice in both open field and hole cross test.Conclusion:This study demonstrates that the treated extract has significant central nervous system depressant effect.Further studies on active constituent of the extract can provide approaches for therapeutic intervention.