Additive anxiolytic-like effect of citicoline and ACPA in the non-acute restraint stress (NARS) and acute restraint stress (ARS) mice.

The cannabinoid system plays a key role in stress-related emotional symptoms such as anxiety. Citicoline is a supplemental substance with neuroprotective properties that alleviates anxiety-related behaviors. There is a relation between the actions of cannabinoids and cholinergic systems. So, we decided to evaluate the effects of intracerebroventricular (i.c.v.) infusion of cannabinoid CB1 receptor agents on citicoline-produced response to anxiety-like behaviors in the non-acute restraint stress (NARS) and acute restraint stress (ARS) mice. For i.c.v. microinjection of drugs, a guide cannula was inserted in the left lateral ventricle. ARS was induced by movement restraint for 4 h. Anxiety-related behaviors were assessed using an elevated plus maze (EPM). The results showed that induction of ARS for 4 h decreased the percentage of time spent in the open arms (%OAT) and the percentage of entries to the open arms (%OAE) without affecting locomotor activity, showing anxiogenic-like behaviors. i.c.v. infusion of ACPA (1 µg/mouse) induced an anxiolytic-like effect due to the enhancement of %OAT in the NARS and ARS mice. Nonetheless, i.c.v. microinjection of AM251 (1 µg/mouse) decreased %OAT in the NARS and ARS mice which suggested an anxiogenic-like response. Intraperitoneal (i.p.) administration of citicoline (80 mg/kg) induced an anxiolytic-like effect by the augmentation of %OAT in the ARS mice. Furthermore, when ACPA and citicoline were co-administrated, ACPA potentiated the anxiolytic-like effect induced by citicoline in the NARS and ARS mice. On the other hand, when AM251 and the citicoline were co-injected, AM251 reversed the anxiolytic-like response induced by the citicoline in the NARS and ARS mice. The results of this research exhibited an additive effect between citicoline and ACPA on the induction of anxiolytic-like response in the NARS and ARS mice. Our results indicated an interaction between citicoline and cannabinoid CB1 receptor drugs on the control of anxiety-like behaviors in the NARS and ARS mice.

Baseline symptom severity and efficacy of Silexan in patients with anxiety disorders: A symptom-based, patient-level analysis of randomized, placebo-controlled trials.

The influence of baseline severity on the efficacy of Silexan, a proprietary essential oil from Lavandula angustifolia, in anxiety disorders has not been investigated in a pooled dataset. We report on an individual patient data analysis of all five double-blind, randomized, placebo-controlled trials with Silexan in anxiety disorders. Eligible participants received Silexan 80 mg/d or placebo for 10 weeks. Analyses were based on the Hamilton Anxiety Rating Scale (HAMA), its psychic and somatic anxiety subscores, and the Clinical Global Impressions (CGI) scale. To correlate baseline severity with outcome, patients were segregated into mild, moderate, and severe cases. Altogether 1,172 patients (Silexan, n = 587; placebo, n = 585) were analyzed. For the HAMA total score, we found a significant association between the score at baseline and the treatment effect of Silexan versus placebo at week 10 (p < 0.001). HAMA items from the somatic domain scored lower at baseline and showed less improvement than items from the psychic domain, particularly in patients with mild or moderate baseline symptoms. For CGI item 2 (global improvement), significant efficacy favoring Silexan were observed in mild, moderate, and severe baseline symptom severity. Although significant improvements were found for all subsets, the more severe the initial symptoms, the greater the treatment effects documented by the HAMA. Overall this analysis confirms that Silexan is an effective treatment option in early or mild stages of anxiety disorder. Given its favorable safety profile, Silexan can thus fill a therapeutic gap in the treatment of (subsyndromal) anxiety disorders.

Bark extract of Chaetocarpus castanocarpus (Roxb.) exhibits potent sedative, anxiolytic, and antidepressant effects through an in vivo approach in Swiss albino mice.

OBJECTIVE: Standard phytochemical investigations were performed to identify the secondary metabolites in the methanol extract of Chaetocarpus castanocarpus bark (MECC) and investigate the neuropharmacological potential of MECC in Swiss albino mice. MATERIALS AND METHODS: Swiss albino mice were used in the forced swimming test (FST) and tail suspension test (TST) to evaluate the antidepressant effect of MECC. Also, the hole board test (HBT) and elevated plus maze (EPM) were conducted to examine anxiolytic activities. In contrast, the open field test (OFT) and hole cross test (HCT) were employed to evaluate sleeping disorders. RESULTS: Alkaloids, glycosides, flavonoids, terpenoids, coumarins, and tannins are only a few secondary metabolites identified in MECC by qualitative and quantitative phytochemical investigations. The oral administration of MECC considerably shortened the immobility duration during FST and TST. Encouraging dose-dependent anxiolytic effects were also observed in all relevant experiments compared to the control. Additionally, during the OFT and HCT assessment, a noteworthy decline in the locomotor activities of the experimental animals was observed. CONCLUSIONS: The results of this investigation suggest that the Chaetocarpus castanocarpus bark is a possible source of therapeutic candidates for treating neurological disorders.

Potential of the Blue Calm® food supplement in the treatment of alcohol withdrawal-induced anxiety in adult zebrafish (Danio rerio).

Alcohol use disorder (AUD) is characterized by a set of behavioral, cognitive, nutritional, and physiological phenomena derived from the uncontrolled use of alcoholic beverages. There are cases in which AUD is associated with anxiety disorder, and when untreated, it requires careful pharmacotherapy. Blue Calm® (BC) is a food supplement indicated to aid restorative sleep, which has traces of medicinal plant extracts, as well as myo-inositol, magnesium bisglycinate, taurine, and L-tryptophan as its main chemical constituents. In this context, this study aimed to evaluate the potential of the BC in the treatment alcohol withdrawal-induced anxiety in adult zebrafish (aZF). Initially, BC was submitted to antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl radical. Subsequently, the aZF (n = 6/group) were treated with BC (0.1 or 1 or 10 mg/mL; 20 µL; p.o.), and the sedative effect and acute toxicity (96 h) were evaluated. Then, the anxiolytic-like effect and the possible GABAergic mechanism were analyzed through the Light & Dark Test. Finally, BC action was evaluated for treating alcohol withdrawal-induced anxiety in aZF. Molecular docking was performed to evaluate the interaction of the major chemical constituents of BC with the GABAA receptor. BC showed antioxidant potential, a sedative effect, was not toxic, and all doses of BC had an anxiolytic-like effect and showed potential for the treatment of alcohol withdrawal-induced anxiety in aZF. In addition to the anxiolytic action, the main chemical constituents of BC were confirmed in the molecular docking, thus suggesting that BC is an anxiolytic that modulates the GABAergic system and has pharmacological potential for the treatment of alcohol withdrawal-induced anxiety.

Studies on neurobehavioural properties of Caralluma dalzielii N.E Br. aqueous aerial parts extract in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Caralluma dalzielii (Asclepiadiaceae) is a shrub used in folkloric medicine to treat epilepsy, pain and infertility in sub-Saharan Africa. Previous studies demonstrated its analgesic, antiulcer, anticonvulsant, and anti-inflammatory activities. AIM: This study aimed to determine the neurobehavioural properties of Caralluma dalzielii aqueous aerial parts extract (CDAE) in mice using standard experimental models. MATERIALS AND METHODS: Neurobehavioural activities of CDAE were evaluated (100, 200, and 400 mg/kg) in Swiss Albino mice using the beam walk, staircase, hole board, object recognition, open field assay, Y-maze and forced swimming tests. Phytochemical constituents were analysed using GC-MS. RESULTS: CDAE significantly increased the mean number of head dips, recognition index and spontaneous alternation in hole board (14.03 at 400 mg/kg and 6.01 in distilled water group; p < 0.05), object recognition (68.16% at 400 mg/kg compared with 51.66% of distilled water group) and Y maze (9.16 at 400 mg/kg as against 4.66 of distilled water group; p < 0.05) tests respectively. It decreased the rearing counts as well as the peripheral and central square crossing in the staircase (4.2 at 400 mg/kg as against 7.87 of the distilled water group; p < 0.05) and open field tests (central, 0.81; peripheral, 1.66 at 400 mg/kg as against central, 5.23; peripheral 11.83 of the distilled water control group; p < 0.05), respectively. There were no significant effects on beam walk assays and forced swim tests. The GC-MS analysis identified a hundred compounds in CDAE. Some compounds which have been reported to possess neurobehavioural activity that were identified include 3,5-Dimethylpyrazole, 2-Amino-5-methylbenzoic acid, Acetophenone, and Tetrahydropyran. CONCLUSION: CDAE demonstrated anxiolytic, anti-hyperactivity, and memory-improving effects in mice. The extract may possess GABAergic and glutamatergic properties. More studies are needed to confirm this. Isolation of the bioactive compounds is currently ongoing to unravel the bioactive constituents present in C. dalzielii extract.

Inhaled Litsea glaucescens K. (Lauraceae) leaves' essential oil has anxiolytic and antidepressant-like activity in mice by BDNF pathway activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Litsea glaucescens K. (Lauraceae) is a small tree from the Mexican and Central American temperate forests, named as "Laurel". Its aromatic leaves are ordinarily consumed as condiments, but also are important in Mexican Traditional Medicine, and among the most important non wood forest products in this area. The leaves are currently used in a decoction for the relief of sadness by the Mazahua ethnic group. Interestingly, "Laurel" has a long history. It was named as "Ehecapahtli" (wind medicine) in pre-Columbian times and applied to heal maladies correlated to the Central Nervous System, among them depression, according to botanical texts written in the American Continent almost five centuries ago. AIM OF THE STUDY: Depression is the first cause of incapacity in the world, and society demands alternative treatments, including aromatherapy. We have previously demonstrated the antidepressant-like activity of L. glaucescens leaves' essential oil (LEO), as well as their monoterpenes linalool, and beta-pinene by intraperitoneal route in a mice behavioral model. Here we now examined if LEO and linalool exhibit this property and anxiolytic activity when administered to mice by inhalation. We also investigated if these effects occur by BDNF pathway activation in the brain. MATERIALS AND METHODS: The LEO was prepared by distillation with water steam and analyzed by gas chromatography-mass spectrometry (GC-MS). The monoterpenes linalool, eucalyptol and ß-pinene were identified and quantified. Antidepressant type properties were determined with the Forced Swim Test (FST) on mice previously exposed to LEO or linalool in an inhalation chamber. The spontaneous locomotor activity and the sedative effect were assessed with the Open Field Test (OFT), and the Exploratory Cylinder (EC), respectively. The anxiolytic properties were investigated with the Elevated Plus Maze Apparatus (EPM) and the Hole Board Test (HBT). All experiments were video documented. The mice were subjected to euthanasia, and the brain hippocampus and prefrontal cortex were dissected. RESULTS: The L. glaucescens essential oil (LEO) contains 31 compounds according to GC/MS, including eucalyptol, linalool and beta-pinene. The LEO has anxiolytic effect by inhalation in mice, as well as linalool, and ß-pinene, as indicated by OFT and EC tests. The LEO and imipramine have antidepressant like activity in mice as revealed by the FST; however, linalool and ketamine treatments didn't modify the time of immobility. The BDNF was increased in FST in mice treated with LEO in both areas of the brain as revealed by Western blot; but did not decrease the level of corticosterone in plasma. The OFT indicated that LEO and imipramine didn't reduce the spontaneous motor activity, while linalool and ketamine caused a significant decrease. CONCLUSION: Here we report by the first time that L. glaucescens leaves essential oil has anxiolytic effect by inhalation in mice, as well as linalool, and ß-pinene. This oil also maintains its antidepressant-like activity by this administration way, similarly to the previously determined intraperitoneally. Since inhalation is a common administration route for humans, our results suggest L. glaucescens essential oil deserve future investigation due to its potential application in aromatherapy.

Assessment of the anxiolytic, antidepressant, and antioxidant potential of Parquetina nigrescens (Afzel.) Bullock in Wistar rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The recent growing concerns about the multisystemic nature of mental health conditions in the global population are facilitating a new paradigm involving alternative natural, nutritional, and complementary therapies. Herbal remedies despite accounts in literature of their ethnobotanical as alternative remedies for diverse ailments, remain underexplored for psychiatric disorders like anxiety, depression, and insomnia. AIM OF THE STUDY: Hence, the anxiolytic, antidepressant, and antioxidant properties of a hydro-ethanolic leaf extract of Parquetina nigrescens (PN) in male Wistar rats were investigated. MATERIALS AND METHODS: The sedative effect was evaluated using the Diazepam sleeping time test while anxiety was induced with a single intraperitoneal injection of 20 mg/kg pentylenetetrazol (PTZ). This was after pre-treatment with 100, 150, and 250 mg/kg of PN or the standard drugs (1 mg/kg diazepam and 30 mg/kg imipramine) for 14 consecutive days. Behavioral tests (Open Field test, Elevated Plus-Maze test, and Forced Swim test) were performed on days 1 and 14, to evaluate the antidepressant and anxiolytic activities of PN. Oxidative stress and neurochemical markers were determined in the brain homogenates of the animals. RESULTS: The duration of sleep was significantly (p < 0.001) increased in the PN-administered group compared to the control. The behavioral models showed that PN exhibited antidepressant and anxiolytic properties in PTZ-induced animals. Significant reductions were observed in GSH level and SOD activity while MDA, nitrite, and GPx levels were significantly increased in PTZ-induced rats. However, treatment with PN significantly improved brain antioxidant status by ameliorating the PTZ-induced oxidative stress. Dopamine, cortisol, and acetylcholine esterase activity levels were significantly (p < 0.05) elevated while serotonin and brain-derived neurotrophic factors were reduced in PTZ-induced rats compared with the control. CONCLUSION: The PN demonstrated neurotransmitter modulatory ability by ameliorating the PTZ-induced neurochemical dysfunction. Findings from this study showed that PN exhibited sedative, antidepressant, and anxiolytic activities in rats.

Anxiolytic interventions of extracts and pure compounds from Adenanthera pavonina and Peltophorum pterocarpum leaves to treat acute anxiety and depression symptoms in mice.

Anxiolytic effect of ethanol, hexane extracts and pure compounds ß- sito sterol glucoside and bergenin isolated from Adenanthera pavonina AP (Fabaceae) and Peltophorum pterocarpum PP (Fabaceae) leaves were monitored in this study. Mice were treated with dose of 125mg/kg body weight of ethanol and hexane leaves extracts of both tested plants while, 5mg/kg body weight of ß-sito sterol glucoside and 25mg/kg body weight of bergenin. The effect was monitored by hole board test, forced swimming test, open field apparatus and stationary rod test. Results from neuropharmacological effects revealed that ethanol extract of AP leaves and hexane extract of PP leaves had significant anxiolytic (forced swimming test) exploratory (head dip and open field test) and neuro activator activity (stationary rod test) at tested dose. The greatest anti-depressant and anxiolytic effect was found in ethanol extract of AP leaves when compared to all treated drugs. A part from memory enhancing effects, diazepam treated mice also exhibited anxiolytic and antidepressant effects and found comparable with ethanol extract of AP. These findings may clarify the impact of ethanol, hexane extracts and pure substances ß-sitosterol glucoside and bergenin at tested concentrations, as well as their potential to treat the Parkinson's and related disorders as an alternative therapy.

Effect of kava (Piper methysticum) on peripheral gene expression among individuals with generalized anxiety disorder: A post hoc analysis of a randomized controlled trial.

Kava is a South Pacific plant-based medicine with anxiolytic properties, but little is known about the impact kava has on gene expression or whether gene expression can serve as a marker of kava response. This study aimed to determine whether kava treatment alters the expression of genes with physiological relevance to anxiety pathophysiology and whether the baseline expression of these physiologically relevant genes modifies the efficacy of kava treatment. In this post hoc analysis, we examined the expression of 48 genes relevant to the pathophysiology of anxiety collected from a double-blind randomized controlled trial that assessed the efficacy of kava treatment in generalized anxiety disorder. Peripheral blood gene expression was measured in 71 (34 kava, 37 placebo) adults at baseline and in 40 (19 kava, 21 placebo) after 8 weeks of treatment by reverse transcription polymerase chain reaction (PCR). Results revealed that kava decreased the expression of a subunit of the GABAA -rho receptor gene (GABRR2) and catechol-O-methyltransferase (COMT), a gene related to catecholamine metabolism. Kava efficacy was not found to be modified by baseline (pretreatment) expression of relevant genes. Although these results did not withstand statistical correction for multiple comparisons and require external validation, they support the notion that kava's mechanism of action includes interaction with GABAergic and catecholaminergic systems.

Pomegranate (Punica granatum L.) and its phytochemicals as anxiolytic; an underreported effect with therapeutic potential: A systematic review.

Anxiety is a mental disorder characterized by excessive concern about possible future threats that, if prolonged, becomes a pathology that must be controlled through psychotherapy and medication. Currently, the pharmacological treatment for anxiety involves the use of antidepressants and benzodiazepines; however, these treatments often come with adverse effects. Thus, there is a need to seek natural compounds that can help alleviate anxiety and reduce these side effects. On the other hand, pomegranate (PG) fruit is known to have important health benefits, which have been compiled in several reviews. However, its anxiolytic effect has not been thoroughly studied, and clinical research on this topic is lacking. The aim of this work was to conduct a systematic review of studies exploring the anxiolytic-like effect of PG and its phytochemicals. Databases such as Pubmed, ScienceDirect, Springer link, Google scholar, Worldwide science, and Web of science were searched for articles using predetermined terms. Inclusion criteria were established, and original articles that met these criteria were selected. The data collected included information on PG part and variety, species, sample size, anxiety model, dose, route and time of administration, reference drug, main results, and the mechanisms of action. Fifty-nine studies were found that reported the anxiolytic-like effect of PG and its phytochemicals such as anthocyanins, flavonoids, tannins, organic acids, and xanthonoids. The literature suggests that the mechanisms of action behind this effect involved the inhibition of the GABAergic receptor, NMDA, CaMKII/CREB pathway; the reduction of oxidative stress, inhibiting TLR4 and nNOS; modulation of cytokines and the expression of NFkB, GAD67, and iNOS, as well as the activation of Nrf2 and AMPK. PG and some of its phytochemicals could be considered as a novel alternative for the treatment of pathological anxiety. This review is the first to document the anxiolytic-like effect of PG.

Coriandrum sativum and Its Utility in Psychiatric Disorders.

The negative impact on worldwide social well-being by the increasing rate of psychiatric diseases has led to a continuous new drug search. Even though the current therapeutic options exert their activity on multiple neurological targets, these have various adverse effects, causing treatment abandonment. Recent research has shown that Coriandrum sativum offers a rich source of metabolites, mainly terpenes and flavonoids, as useful agents against central nervous system disorders, with remarkable in vitro and in vivo activities on models related to these pathologies. Furthermore, studies have revealed that some compounds exhibit a chemical interaction with γ-aminobutyric acid, 5-hydroxytryptamine, and N-methyl-D-aspartate receptors, which are key components in the pathophysiology associated with psychiatric and neurological diseases. The current clinical evaluations of standardized extracts of C. sativum are scarce; however, one or more of its compounds represents an area of opportunity to test the efficacy of the plant as an anxiolytic, antidepressant, antiepileptic, or sleep enhancer. For this, the aim of the review was based on the pharmacological activities offered by the compounds identified and isolated from coriander and the processes involved in achieving their effect. In addition, lines of technological research, like molecular docking and nanoparticles, are proposed for the future development of phytomedicines, based on the bioactive molecules of C. sativum, for the treatment of psychiatric and neurological disorders addressed in the present study.

Harmine exerts anxiolytic effects by regulating neuroinflammation and neuronal plasticity in the basolateral amygdala.

Increasing evidence indicates that an altered immune system is closely linked to the pathophysiology of anxiety disorders, and inhibition of neuroinflammation may represent an effective therapeutic strategy to treat anxiety disorders. Harmine, a beta-carboline alkaloid in various medicinal plants, has been widely reported to display anti-inflammatory and potentially anxiolytic effects. However, the exact underlying mechanisms are not fully understood. Our recent study has demonstrated that dysregulation of neuroplasticity in the basolateral amygdala (BLA) contributes to the pathological processes of inflammation-related anxiety. In this study, using a mouse model of anxiety challenged with Escherichia coli lipopolysaccharide (LPS), we found that harmine alleviated LPS-induced anxiety-like behaviors in mice. Mechanistically, harmine significantly prevented LPS-induced neuroinflammation by suppressing the expression of pro-inflammatory cytokines including IL-1ß and TNF-α. Meanwhile, ex vivo whole-cell slice electrophysiology combined with optogenetics showed that LPS-induced increase of medial prefrontal cortex (mPFC)-driven excitatory but not inhibitory synaptic transmission onto BLA projection neurons, thereby alleviating LPS-induced shift of excitatory/inhibitory balance towards excitation. In addition, harmine attenuated the increased intrinsic neuronal excitability of BLA PNs by reducing the medium after-hyperpolarization. In conclusion, our findings provide new evidence that harmine may exert its anxiolytic effect by downregulating LPS-induced neuroinflammation and restoring the changes in neuronal plasticity in BLA PNs.

Anxiolytic-like Effects and Quantitative EEG Profile of Palmitone Induces Responses Like Buspirone Rather Than Diazepam as Clinical Drugs.

Anxiety is a mental disorder with a growing worldwide incidence due to the SARS-CoV-2 virus pandemic. Pharmacological therapy includes drugs such as benzodiazepines (BDZs) or azapirones like buspirone (BUSP) or analogs, which unfortunately produce severe adverse effects or no immediate response, respectively. Medicinal plants or their bioactive metabolites are a shared global alternative to treat anxiety. Palmitone is one active compound isolated from Annona species due to its tranquilizing activity. However, its influence on neural activity and possible mechanism of action are unknown. In this study, an electroencephalographic (EEG) spectral power analysis was used to corroborate its depressant activity in comparison with the anxiolytic-like effects of reference drugs such as diazepam (DZP, 1 mg/kg) and BUSP (4 mg/kg) or 8-OH-DPAT (1 mg/kg), alone or in the presence of the GABAA (picrotoxin, PTX, 1 mg/kg) or serotonin 5-HT1A receptor antagonists (WAY100634, WAY, 1 mg/kg). The anxiolytic-like activity was assayed using the behavioral response of mice employing open-field, hole-board, and plus-maze tests. EEG activity was registered in both the frontal and parietal cortex, performing a 10 min baseline and 30 min recording after the treatments. As a result, anxiety-like behavior was significantly decreased in mice administered with palmitone, DZP, BUSP, or 8-OH-DPAT. The effect of palmitone was equivalent to that produced by 5-HT1A receptor agonists but 50% less effective than DZP. The presence of PTX and WAY prevented the anxiolytic-like response of DZP and 8-OH-DPAT, respectively. Whereas only the antagonist of the 5-HT1A receptor (WAY) inhibited the palmitone effects. Palmitone and BUSP exhibited similar changes in the relative power bands after the spectral power analysis. This response was different to the changes induced by DZP. In conclusion, brain electrical activity was associated with the anxiolytic-like effects of palmitone implying a serotoninergic rather than a GABAergic mechanism of action.

Integration of non-targeted metabolomics with network pharmacology deciphers the anxiolytic mechanisms of Platycladi Semen extracts in CUMS mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Platycladi Semen was recorded in Shen Nong's Herbal Classic and was considered a herbal medicine with low toxicity after long-term medication. Multiple traditional Chinese medicine prescriptions containing Platycladi Semen have been used to treat insomnia. Modern clinical practitioners commonly use Platycladi Semen to treat anxiety disorders, but there are few studies on its composition and anxiolytic mechanisms. AIM OF THE STUDY: To describe the main components of Platycladi Semen and investigate its anxiolytic effects and mechanisms. MATERIALS AND METHODS: The main components of Platycladi Semen were characterized by liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS). The anxiolytic effects of oral Platycladi Semen were evaluated in chronic unpredictable mild stress (CUMS) induced mice. To explore the anxiolytic mechanisms of Platycladi Semen, serum non-targeted metabolomics combined with network pharmacology and molecular docking was performed. RESULTS: Fourteen compounds were identified in the 50% methanol extract and 11 fatty acid derivatives were identified in the methyl-esterified fatty oil of Platycladi Semen. In CUMS mice, both the aqueous extract and fatty oil of Platycladi Semen had anxiolytic effects, which were shown by the increase in the time and frequency of mice entering the open arm in the elevated plus maze (EPM) experiment. Through serum non-targeted metabolomics, 34 differential metabolites were identified, and lipid metabolic pathways such as sphingolipid metabolism, steroidogenesis, alpha-linoleic acid, and linoleic acid metabolism were enriched. Through network pharmacology, 109 targets of the main components in Platycladi Semen were identified, and the 'neuroactive ligand-receptor interaction' and 'lipid metabolism' were enriched. The molecular docking results showed that the main components in Platycladi Semen could bind to the key targets such as peroxisome proliferator-activated receptor delta (PPARD), peroxisome proliferator-activated receptor alpha (PPARA), fatty acid binding protein 5 (FABP5), fatty acid binding protein 3 (FABP3), peroxisome proliferator-activated receptor gamma (PPARG), arachidonate 5-lipoxygenase (ALOX5) and fatty acid amide hydrolase (FAAH). CONCLUSION: This study indicated that Platycladi Semen has anxiolytic effects, and the anxiolytic mechanisms may be the regulation of lipid metabolism and the neuroactive ligand-receptor interaction.

The potential of lemon balm (Melissa officinalis L.) essential oil as an anti-anxiety agent - is the citronellal the activity carrier?

ETHNOPHARMACOLOGICAL RELEVANCE: Among the fewest drugs discovered are those belonging to the class of anxiolytics. Although some drug targets for anxiety disorders are established, it is hard to modify and selectively choose the active principle for those targets. Thus, the ethnomedical approach to treating anxiety disorders remains one of the most prevalent ways for (self)managing the symptoms. Melissa officinalis L. (lemon balm) has been extensively used as an ethnomedicinal remedy for the treatment of different psyche-related symptoms, especially dose related to restlessness. AIM OF THE STUDY: This work aimed to evaluate the anxiolytic activity, in several in vivo models, of the essential oil extracted from Melissa officinalis (MO) and its main constituent citronellal, a widespread plant utilized for managing anxiety. MATERIALS AND METHODS: In the present study several animal models were used to assess MO anxiolytic potential in mice. The effect of the MO essential oil applied in doses ranging from 12.5 to 100 mg/kg was estimated in light/dark, hole board, and marble burying tests. In parallel doses of citronellal corresponding to the ones in the MO essential oil were applied to animals to determine if this is the activity carrier. RESULTS: The results indicate that the MO essential oil exerts anxiolytic potential in all three experimental settings by significantly altering the traced parameters. The effects of citronellal are somewhat inconclusive and should not be interpreted only as anxiolytic but rather as a combination of anti-anxiety and motor-inhibiting effects. CONCLUSIONS: In conclusion, we could say that the results of the present study provide a base for future mechanistic studies that would evaluate the activity of M. officinalis essential oil on various neurotransmitter systems involved in the generation, propagation, and maintenance of anxiety.

Systematic review on the anxiolytic and hypnotic effects of flower extracts in in vivo pre-clinical studies published from 2010 to 2020.

Anxiety disorders are prevalent conditions in the world population, whose standard approaches include pharmacotherapy, psychotherapy, and combinations of these interventions. Different classes of psychopharmaceuticals are recommended as the first line of drugs to treat these disorders, which can have several adverse effects, treatment resistance, dependence, and drug-drug interactions making it necessary to search for new therapeutic agents. In particular, diazepam (DZP), a prototype drug from the group of benzodiazepines, has been commonly used and evaluated for its efficacy and safety in different anxiety disorders in clinical trials. DZP is also the most widely used reference standard in in vivo pharmacological assays of natural compounds. However, translating the results obtained in different rodent species and physiological anxiety tests instead of psychopathological animal models that can be of clinical application remains challenging. A systematic review of scientific articles published between 2010 and 2020 that included in vivo pre-clinical tests to define the anxiolytic, sedative and/or hypnotic effect of flower extracts is proposed. PRISMA and Rayyan were used for the selection of studies using four databases (Pubmed, Scopus, Web of Science, and QInsight), using the keywords: "Animals," "Anxiolytic," "Diazepam," "Elevated Plus Maze," "Flower Extracts," "Insomnia," "In vivo," "Mice," "Open Field Test," "Pre clinical" and "Sedative." The characteristics of anxiety studies in animal models, other studies related to locomotor activity, and the hypnotic effect of the extracts were compiled. Twenty-four articles were included, 21 of them performed the animal model of anxiety-like behavior of the elevated plus maze, seven the open field test, and six the light-dark box test. The locomotor activity was evaluated in 10 studies after the administration of the extracts to the animals to define their sedative effect, where only one defined that the extract (Matricaria chamomilla) had a sedative effect. The plants declared with this type of activity were Achyranthes aspera, Alcea aucheri, Brassica nigra, Cananga odorata, Carthamus tinctorius, Chrysanthemum indicum, Citrus aurantium, Couroupita guianensis, Echium amoenum, Erythrina berteroana, Gardenia jasminoides, Hibiscus tilliaceus, Lavandula officinalis, Lawsonia inermis, Matricaria chamomilla, Melia azedarach, Nerium oleander, Passiflora incarnata, Plumeria rubra, Salix aegyptiaca, Syzygium aromaticum, Tagetes erecta, Tilia americana. Although this review showed that some flower extracts have an anxiolytic effect as effective as diazepam, their therapeutic utility in anxiety disorders remains to be extensively demonstrated. Hence, more reliable and predictive behavioral tests and appropriate strategies for the experimental designs are needed to obtain more conclusive evidence with clinical significance.

In Vivo Neuropharmacological Effects of Neophytadiene.

Neophytadiene (NPT) is a diterpene found in the methanolic extracts of Crataeva nurvala and Blumea lacera, plants reported with anxiolytic-like activity, sedative properties, and antidepressant-like actions; however, the contribution of neophytadiene to these effects is unknown. This study determined the neuropharmacological (anxiolytic-like, antidepressant-like, anticonvulsant, and sedative) effects of neophytadiene (0.1-10 mg/kg p.o.) and determined the mechanisms of action involved in the neuropharmacological actions using inhibitors such as flumazenil and analyzing the possible interaction of neophytadiene with GABA receptors using a molecular docking study. The behavioral tests were evaluated using the light-dark box, elevated plus-maze, open field, hole-board, convulsion, tail suspension, pentobarbital-induced sleeping, and rotarod. The results showed that neophytadiene exhibited anxiolytic-like activity only to the high dose (10 mg/kg) in the elevated plus-maze and hole-board tests, and anticonvulsant actions in the 4-aminopyridine and pentylenetetrazole-induced seizures test. The anxiolytic-like and anticonvulsant effects of neophytadiene were abolished with the pre-treatment with 2 mg/kg flumazenil. In addition, neophytadiene showed low antidepressant effects (about 3-fold lower) compared to fluoxetine. On other hand, neophytadiene had no sedative or locomotor effects. In conclusion, neophytadiene exerts anxiolytic-like and anticonvulsant activities with the probable participation of the GABAergic system.

Ethnopharmacological evaluation of Poppy seed oil in combination with Tramadol on behavioral paradigm and on dopamine, and cytokines levels.

OBJECTIVE: The present study was taken up to evaluate the combination of two drugs in the management of behavioral disorders such as locomotor activity, muscle relaxation, analgesic, and anxiolytic activity. MATERIALS AND METHODS: In the methodology, Wistar rats weighing (150-180 g) were divided into six groups of 6 each (n=6). All the animals (groups II to VI) were subjected to stress and analyzed for anxiolytic activity using an elevated plus maze. The animals were treated for 28 days with poppy seed oil in lower and higher doses (1,000 and 2,000 mg/kg), tramadol in lower and higher doses (1.5 and 3 mg/kg) as individual groups, and one group with a combination of both drugs in lower doses. RESULTS: The results depicted showed that the combined treatment had significantly (**p <0.001) improvised behavior deficits, extemporized, and diminished anxiety-like attitude in rats, and showed the analgesic property in a significant manner. The pro-inflammatory cytokines TNF-α and IL-1ß were evaluated in the serum and were observed to be lessened the values of both in a significant manner with the co-administration of both the test drugs. The dopamine concentrations were also determined in the serum, which disclosed a decline (**p <0.001) significantly. CONCLUSIONS: It was concluded from the results that a combined effect of drugs might be beneficial in the management of behavioral disorders and pain management.

Evaluation of CNS Depressant and Anti-anxiety Activities of Leaves of Convolvulus pluricaulis.

BACKGROUND: Convolvulus pluricaulis is a native plant that is commonly mentioned in Ayurveda as a Rasayana and is primarily recommended for use in mental stimulation and rejuvenation therapy. Convolvulus pluricaulis is used as a brain tonic. The plant is reported to be a prominent memory-improving drug. It is used as a psychostimulant and tranquilizer. It is reported to reduce mental tension. OBJECTIVE: The present study aimed to explore the protective effect of hydroalcoholic extract from the leaves of Convolvulus pluricaulis along with CNS depressant and anti-anxiety activities, in models of mice. METHODS: The extract from leaves of Convolvulus pluricaulis were sequentially isolated with a mixture of water and alcohol solution in the soxhlet apparatus. An acute toxicity study was conducted as per OECD guidelines no. 423, in which 18 Albino male mice were treated with different doses (1, 10, 100, 500, 1000, and 2000 mg/kg) of hydroalcoholic extract of Convolvulus pluricaulis and assessed for toxicity parameters for 14 days. Various psychomotor activities of hydroalcoholic extract from leaves of Convolvulus pluricaulis for 100, 200, and 300 mg/kg doses were performed in mice by using various tests like actophotometer, open field, rota-rod, grip strength tests, elevated plus maze, hole board test, inclined plane, chimney test. RESULTS: The hydroalcoholic extract from leaves of Convolvulus pluricaulis was found to fall under category 4 in the acute toxicity study. Therefore, 100, 200, and 300 mg/kg doses of hydroalcoholic extract of leaves of Convolvulus pluricaulis were selected for the further pharmacological study. The results of psychomotor tests (actophotometer, open field, rota-rod, grip strength, hole board test, inclined plane, chimney test, elevated plus maze, light-dark model) for test doses 100, 200, and 300 in mice showed CNS depressant and anti-anxiety effects. CONCLUSION: Hydroalcoholic extract from leaves of Convolvulus pluricaulis at the 100, 200, and 300 mg/kg doses has shown CNS depressant and anti-anxiety effects in mice models.