Ethnomedicinal Study and Evaluation of the Anxiolytic-like and Diuretic Effects of the Orchid Stanhopea tigrina Bateman ex Lindl-(Orchidaceae).

Stanhopea tigrina Bateman ex Lindl. (Orchidaceae) is an orchid endemic to Mexico, known as "Calavera" or "calaverita", in the Huasteca Potosina (central region of Mexico). This plant species is used for the folk treatment of mental disorders and urological kidney disorders, according to the ethnomedicinal information obtained in this study. Ethanolic extracts of leaves (HE) and pseudobulb (PE) were obtained by microwave-assisted extraction (MAE). Gas Chromatography coupled with Mass Spectrometry (GC-MS) was used to carry out the chemical characterization of HE and PE. The pharmacological effects (antioxidant, diuretic, anxiolytic, locomotor, hypnotic, and sedative) of HE and PE were evaluated. The possible mechanism of action of the anxiolytic-like activity induced by HE was assessed using inhibitors of the GABAergic, adrenergic, and serotonergic systems. The possible mechanism of the diuretic action of HE was assessed using prostaglandin inhibitory antagonists and nitric oxide synthase (NOS) blockers. HE at 50 and 100 mg/kg exerted anxiolytic-like activity without inducing hypnosis or sedation. Flumazenil, prazosin, and ketanserin inhibited the anxiolytic-like activity shown by HE, which suggests the participation of GABA, α1-adrenergic receptors, and 5-HT2 receptors, respectively. The diuretic effect was reversed by the non-selective NOS inhibitor L-NAME, which caused the reduction in nitric oxide (NO). These results demonstrate that the ethanolic extract of S. tigrina leaves exhibited anxiolytic-like activity and diuretic effects without inducing hypnosis or sedation. This work validates the medicinal uses of this orchid species.

The novel non-hallucinogenic compound DM506 (3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole) induces sedative- and anxiolytic-like activity in mice by a mechanism involving 5-HT2A receptor activation.

The anxiolytic and sedative-like effects of 3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (DM506), a non-hallucinogenic compound derived from ibogamine, were studied in mice. The behavioral effects were examined using Elevated O-maze and novelty suppressed feeding (NSFT) tests, open field test, and loss of righting reflex (LORR) test. The results showed that 15 mg/kg DM506 induced acute and long-lasting anxiolytic-like activity in naive and stressed/anxious mice, respectively. Repeated administration of 5 mg/kg DM506 did not cause cumulative anxiolytic activity or any side effects. Higher doses of DM506 (40 mg/kg) induced sedative-like activity, which was inhibited by a selective 5-HT2A receptor antagonist, volinanserin. Electroencephalography results showed that 15 mg/kg DM506 fumarate increased the transition from a highly alert state (fast γ wavelength) to a more synchronized deep-sleeping activity (δ wavelength), which is reflected in the sedative/anxiolytic activity in mice but without the head-twitch response observed in hallucinogens. The functional, radioligand binding, and molecular docking results showed that DM506 binds to the agonist sites of human 5-HT2A (Ki = 24 nM) and 5-HT2B (Ki = 16 nM) receptors and activates them with a potency (EC50) of 9 nM and 3 nM, respectively. DM506 was relatively less potent and behaved as a partial agonist (efficacy <80%) for both receptor subtypes compared to the full agonist DOI (2,5-dimethoxy-4-iodoamphetamine). Our study showed for the first time that the non-hallucinogenic compound DM506 induces anxiolytic- and sedative-like activities in naïve and stressed/anxious mice in a dose-, time-, and volinanserin-sensitive manner, likely through mechanisms involving 5-HT2A receptor activation.

Computational Studies and Synthesis of New Heterocyclics as CNS Agents.

AIM: This research work aimed to design and synthesize some new molecules of phenothiazine. The work's emphasis was on forming new phenothiazines in two series, 1-(10H-phenothiazin-10-yl)-2-((4-(1-(phenylimino)ethyl)phenyl)amino)ethan-1-one derivatives (4a-4j) and 1-(4-((2-oxo-2-(10H-phenothiazin-10-yl)ethyl)amino)phenyl)-3-phenylprop-2-en-1-one derivatives (P1-P5). METHODS: Chloroacetylation of phenothiazine was done to afford 2-chloro-1-(10H-phenothiazin-10-yl)ethan-1-one, which was further reacted with 4-amino acetophenone to produce 2-((4-acetylphenyl)amino)-1-(10H-phenothiazin-10-yl)ethan-1-one. Then, it was treated with substituted anilines and substituted benzaldehydes to produce the final derivatives 4a-4j and P1-P5, respectively. RESULTS: All 15 derivatives (4a-4j and P1-P5) were characterized by evaluating their Rf value, melting point, solubility, IR spectroscopy, and 1HNMR spectroscopy. Molecular docking was performed by using AutoDock Vina v.1.2.0 (The Scripps Research Institute, La Jolla, CA, USA) docking software, and the anxiolytic activity of the derivatives was assessed by using the elevated plus maze model. CONCLUSION: The designed scheme was executed in the departmental laboratory. The chemical structure of the compounds was confirmed on the basis of TLC, IR, and 1HNMR analyses. The docking study revealed a good docking score of the compounds. The Log P value of the compounds indicated their good penetration into CNS. The compounds were also screened for anxiolytic activity. Among them, compounds 4f, 4h, and P3 showed maximum activity as anti-anxiolytic agents.

Coronaridine congeners induce sedative and anxiolytic-like activity in naïve and stressed/anxious mice by allosteric mechanisms involving increased GABAA receptor affinity for GABA.

The sedative and anxiolytic-like activity of two coronaridine congeners, (+)-catharanthine and (-)-18-methoxycoronaridine (18-MC), was studied in male and female mice. The underlying molecular mechanism was subsequently determined by fluorescence imaging and radioligand binding experiments. The loss of righting reflex and locomotor activity results showed that both (+)-catharanthine and (-)-18-MC induce sedative effects at doses of 63 and 72 mg/kg in a sex-independent manner. At a lower dose (40 mg/kg), only (-)-18-MC induced anxiolytic-like activity in naïve mice (elevated O-maze test), whereas both congeners were effective in mice under stressful/anxiogenic conditions (light/dark transition test) and in stressed/anxious mice (novelty-suppressed feeding test), where the latter effect lasted for 24 h. Coronaridine congeners did not block pentylenetetrazole-induced anxiogenic-like activity in mice. Considering that pentylenetetrazole inhibits GABAA receptors, this result supports a role for this receptor in the activity mediated by coronaridine congeners. Functional and radioligand binding results showed that coronaridine congeners interact with a site different from that for benzodiazepines, increasing GABAA receptor affinity for GABA. Our study showed that coronaridine congeners induce sedative and anxiolytic-like activity in naïve and stressed/anxious mice in a sex-independent fashion, likely by a benzodiazepine-independent allosteric mechanism that increases GABAA receptor affinity for GABA.

Jiawei Xiaoyao San in treatment of anxiety disorder and anxiety: A review.

Jiawei Xiaoyao San (JWXYS) has shown excellent clinical efficacy in anxiety disorder, but has not yet attracted widespread attention. The animal experiments, clinical trials and mechanism studies of JWXYS were reviewed in this article, which may provide a reference for developing new anxiolytic drugs based on this prescription. The literature was searched in PubMed and CNKI and the documents written in English or with English abstracts were selected. JWXYS could reduce the anxiety symptoms of patients alone and reduce the adverse reactions when it is used in combination with other drugs in the clinic. In preclinical studies, JWXYS also showed therapeutic effects in reducing anxiety-like behavior. The mechanisms may include improving the hypothalamic-pituitaryadrenal (HPA) axis and hormone disorders, increasing neurotransmitter content, neurogenesis, and regulating the synthesis of related enzymes. This article shows that JWXYS could effectively treat anxiety disorders by regulating the central nervous system. In the future, with the participation of more researchers, it is expected to develop innovative drugs for the treatment of anxiety disorders based on JWXYS.

Lasia spinosa (L.) thw. attenuates chemically induced behavioral disorders in experimental and computational models.

Lasia spinosa (L.) Thw. (L. spinosa) is widely used as a folk remedy for different physical ailments, and its neurological effects have yet to be assessed. Phytochemicals status of L. spinosa was evaluated by GC-MS analysis. Membrane stabilization test, elevated plus maze (EPM) tests and hole board tests (HBT), tail suspension tests (TST) and thiopental sodium-induced sleeping tests (TISTT) were used to assess anti-inflammatory, anxiolytic and anti-depressant activity. Fourteen compounds have been recorded from GC-MS analysis. The LSCTF showed 68.66 ± 2.46% hemolysis protections (p < 0.05) at 500 µg/mL, whereas LSCHF and LSNHF demonstrated efficiency rates of 68.6 ± 1.46% and 52.46 ± 5.28%, respectively. During EPM tests, LSNHF and LSCTF significantly (p < 0.001) increased the time spent in the open arm (59.88 ± 0.65 s and 50.77 ± 0.67 s, respectively) at the dosages of 400 mg/kg. In HBT, samples exhibited dose-dependent anxiolytic activity. LSNHF and LSCTF showed a significant (p < 0.001) hole poking tendency and a high number of head dips (78.66 ± 1.05 and 65.17 ± 0.96, respectively) at the higher dose. In TST, at 400 mg/kg dose demonstrated significantly (p < 0.001) smaller amounts of time immobile, at 81.33 ± 1.67 s and 83.50 ± 1.90 s, respectively, compared to the control group. A consistent finding was also observed in TISTT. The computer-assisted studies on the identified compounds strongly support the aforementioned biological activities, indicating that L. spinosa has potential as a source of medication for treating neuropsychiatric and inflammatory diseases.

Consensus Ensemble Multitarget Neural Network Model of Anxiolytic Activity of Chemical Compounds and Its Use for Multitarget Pharmacophore Design.

A classification consensus ensemble multitarget neural network model of the dependence of the anxiolytic activity of chemical compounds on the energy of their docking in 17 biotargets was developed. The training set included compounds thathadalready been tested for anxiolytic activity and were structurally similar to the 15 studied nitrogen-containing heterocyclic chemotypes. Seventeen biotargets relevant to anxiolytic activity were selected, taking into account the possible effect on them of the derivatives of these chemotypes. The generated model consistedof three ensembles of artificial neural networks for predicting three levels of anxiolytic activity, with sevenneural networks in each ensemble. A sensitive analysis of neurons in an ensemble of neural networks for a high level of activity made it possible to identify four biotargets ADRA1B, ADRA2A, AGTR1, and NMDA-Glut, which were the most significant for the manifestation of the anxiolytic effect. For these four key biotargets for 2,3,4,5-tetrahydro-11H-[1,3]diazepino[1,2-a]benzimidazole and [1,2,4]triazolo[3,4-a][2,3]benzodiazepine derivatives, eight monotarget pharmacophores of high anxiolytic activity were built. Superposition of monotarget pharmacophores built two multitarget pharmacophores of high anxiolytic activity, reflecting the universal features of interaction 2,3,4,5-tetrahydro-11H-[1,3]diazepino[1,2-a]benzimidazole and [1,2,4]triazolo[3,4-a][2,3]benzodiazepine derivatives with the most significant biotargets ADRA1B, ADRA2A, AGTR1, and NMDA-Glut.

Lavandula x intermedia-A Bastard Lavender or a Plant of Many Values? Part II. Biological Activities and Applications of Lavandin.

This review article is the second in a series aimed at providing an in-depth overview of Lavandula x intermedia (lavandin). In part I, the biology and chemistry of lavandin were addressed. In part II, the focus is on the functional properties of lavandin and its applications in industry and daily life. While reviewing the biological properties, only original research articles employing lavandin were considered. Lavandin essential oil has been found to have antioxidant and biocidal activity (antimicrobial, nematicidal, antiprotozoal, insecticidal, and allelopathic), as well as other potential therapeutic effects such as anxiolytic, neuroprotective, improving sleep quality, antithrombotic, anti-inflammatory, and analgesic. Other lavandin preparations have been investigated to a much lesser extent. The research is either limited or inconsistent across all studies, and further evidence is needed to support these properties. Unlike its parent species-Lavandula angustifolia (LA)-lavandin essential oil is not officially recognized as a medicinal raw material in European Pharmacopeia. However, whenever compared to LA in shared studies, it has shown similar effects (or even more pronounced in the case of biocidal activities). This suggests that lavandin has similar potential for use in medicine.

Jiawei Xiaoyao San in treatment of anxiety disorder and anxiety: A review / 中草药·英文版

Jiawei Xiaoyao San (JWXYS) has shown excellent clinical efficacy in anxiety disorder, but has not yet attracted widespread attention. The animal experiments, clinical trials and mechanism studies of JWXYS were reviewed in this article, which may provide a reference for developing new anxiolytic drugs based on this prescription. The literature was searched in PubMed and CNKI and the documents written in English or with English abstracts were selected. JWXYS could reduce the anxiety symptoms of patients alone and reduce the adverse reactions when it is used in combination with other drugs in the clinic. In preclinical studies, JWXYS also showed therapeutic effects in reducing anxiety-like behavior. The mechanisms may include improving the hypothalamic-pituitaryadrenal (HPA) axis and hormone disorders, increasing neurotransmitter content, neurogenesis, and regulating the synthesis of related enzymes. This article shows that JWXYS could effectively treat anxiety disorders by regulating the central nervous system. In the future, with the participation of more researchers, it is expected to develop innovative drugs for the treatment of anxiety disorders based on JWXYS.

New insights on the phytochemical intervention for the treatment of neuropsychiatric disorders using the leaves of Michelia champaca: an in vivo and in silico approach.

CONTEXT: Michelia champaca L. (Magnoliaceae) has been known since ancient times for its rich medicinal properties. OBJECTIVE: The ethanol extract of Michelia champaca leaves (EEMC) was evaluated on depression and anxiety using in vivo and in silico studies. MATERIALS AND METHODS: Swiss albino mice were divided into control, standard, 100 and 200 mg/kg b.w. EEMC groups and for drug administration using oral gavage. The antidepressant activity was evaluated using forced swim test (FST) and tail suspension test (TST) whereas the anxiolytic activity through elevated plus maze and light and dark tests. The in silico studies included molecular docking against human potassium channel KCSA-FAB and human serotonin transporter, and ADME/T analysis. RESULTS: Open arm duration and entries were comparable between 200 mg/kg b.w. group (184.45 ± 1.00 s and 6.25 ± 1.11, respectively) and that of diazepam treated group (180.02 s ± 0.40 and 6.10 ± 0.05, respectively). Time spent in the light cubicle was higher (46.86 ± 0.03%), similar to that of diazepam (44.33 ± 0.64%), suggesting its potent anxiolytic activity. A delayed onset of immobility and lowered immobility time was seen at both the treatment doses (FST: 93.7 ± 1.70 and 89.1 ± 0.40 s; TST: 35.05 ± 2.75 and 38.50 ± 4.10 s) and the standard drug imipramine (FST: 72.7 ± 3.72 and TST: 30.01 ± 2.99 s), indicative of its antidepressant ability. In silico studies predicted doripenem to induce anxiolytic and antidepressant activity by inhibiting human potassium channel KCSA-FAB and human serotonin transporter proteins, respectively. CONCLUSIONS: EEMC is a rich source of bioactive compounds with strong antidepressant and anxiolytic properties.

A comparative evaluation of cardiac and neurological safety status of two commonly used oral hypoglycaemic agents in T2-DM Swiss albino mice model.

Background: Diabetes mellitus (DM), along with its associated complications, including diabetic neuropathy and hyperlipidemia, has become a global concern in the last few decades. The main objective of our study is to evaluate the comparative neuro-safety status, serum plasma glucose, and lipid-lowering potential of two widely recognized antidiabetic drugs named metformin and glimepiride. Methods: The neurological evaluation was done by open field test, hole board test, forced swimming test, dark and lighthouse test, and elevated plus maze test by employing diazepam as standard. Serum blood glucose level of streptozotocin (STZ)-induced diabetic mice was determined by glucose oxidizing method using a glucometer. Total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and very-low-density lipoprotein cholesterol (VLDL-C) levels were estimated by using the reference method where atorvastatin was used as standard. Results: In neurological evaluation, both drugs produce almost the same anxiolytic activity in the open field test, hole board test, light and dark house test, and elevated plus maze test. However, in the forced swimming test, glimepiride produced more antidepressant activity than metformin. Glimepiride was found to remarkably reduce serum glucose and VLDL-C levels more than metformin, whereas, for other parameters, metformin takes over glimepiride sometimes took over the standard atorvastatin. Conclusions: The results of our study indicate that both oral hypoglycaemic drugs alter the lipid index while producing some anxiolytic effects on the central nervous system. Thus, recommended to be carefully administered to patients with low BMI and might be beneficial to patients suffering from peripheral nerve function and anxiety.

Anxiolytic and antidepressant-like activities of aqueous extract of Azadirachta indica A. Juss. flower in the stressed rats.

The aim of this study was to evaluate whether an aqueous extract of Azadirachta indica A. Juss. (A. indica) flower had anxiolytic and antidepressant-like effects in the stressed rats. Male Wistar rats were randomly allocated to one of two experimental groups: control or stress. The stress groups were received restraint stress for 3 h. The stressed rats were administered a vehicle, diazepam, fluoxetine, and A. indica at doses of 250, 500, and 1000 mg/kg BW for 30 days. The elevated plus-maze test (EPMT), the forced swimming test (FST), and the open field test (OFT) were used to assess anxiolytic and antidepressant-like behaviors. In the EPMT, the percentage of the number of open arm entries and the duration spent in open arms were measured. These measurements were considerably enhanced in the stressed rats treated with diazepam and A. indica flower extract at a dose of 500 mg/kg BW. Furthermore, the stressed rats given fluoxetine and A. indica flower extract at all doses employed in this study showed a significant reduction in the amount of time the rats were immobilized in the FST. However, there was no significant difference in spontaneous locomotor activity between any of the groups. Additionally, the stressed rats treated with either positive control medications or A. indica flower extract exhibited significantly higher brain dopamine (DA) and serotonin (5-HT) levels, but lower blood cortisol levels as compared to the stressed rats treated with vehicle. Moreover, A. indica flower extract had no harmful effect on the stressed rats' liver tissue.

Design, synthesis, structural and molecular characterization, toxicity, psychotropic activity and molecular docking evaluation of a novel phenytoin derivative: 3-decyl-5,5-diphenylimidazolidine-2,4-dione.

The hydantoin scaffold is of substantial importance and it is commonly used in drug discovery. Herein, we report the synthesis of a novel phenytoine (a hydantoin derivative) with high yield by the reaction of phenytoin with 1-bromodecyl agent. Namely, 3-decyl-5,5- diphenylimidazolidine-2,4-dione (3DDID). The optimized geometry of the compound was calculated using density functional theory (DFT) method by B3LYP with 6-311++G(d,p) basis set. For this calculation, the X-ray data were used as initial values. Molecular electrostatic potential (MEP) surface and Frontier molecular orbitals (FOMs) were prepared for the compound. The crystal structure of the title compound contains intermolecular N-H···O, C-H···O hydrogen bonds and weak C-H···π interactions. Hirshfeld surface analysis and 2D fingerprint plots of the molecule aid comparison of intermolecular interactions and these analysis reveals that two close contacts are associated with intermolecular hydrogen bonds. The psychotropic activity evaluation of the synthesized compound was further explored using hole bored test for exploratory behaviors, dark//light box test for anxiolytic activity and Rota-road, traction, chimney testes were used to assess the myrelaxant effect. In addition, molecular modeling study was also conducted to rationalize the potential as neurotherapeutic drugs of our synthesized compound by predicting their binding modes, binding affinities and optimal orientation at the active site of the GABA-A receptor and Na+ channel. Finally, in silico ADMET predictions was also examined. HighlightsSynthesis, structural, and molecular characterization of a novel phenytoin derivative.DFT, XRD, and the Hirshfeld surface analysis of crystal structure was studied.Acute toxicity and psychotropic activity evaluation of 3-decyl-5,5 diphenylimidazolidine-2,4-dione (3DDID).Molecular modeling studies have been conducted to rationalize the obtained data and to determine the probable binding mode.Communicated by Ramaswamy H. Sarma.

Design, Synthesis and Pharmacological Activity of New Pyrrolo[1,2-A] Pyrazine Translocator Protein (TSPO) Ligands.

BACKGROUND: Translocator protein 18 kDa (TSPO) is a promising target for the creation of effective and safe neuropsychotropic drugs. The ligands of TSPO exhibit anxiolytic, antidepressant, neuroprotective and other activities without the side effects of benzodiazepines. METHODS: New TSPO ligands in the series of N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamides derivatives were designed using calculated pharmacophore model and molecular docking analysis. The synthesis of new compounds was carried out by two schemes using [3+3]-cycloaddition reaction of 2-azidoacrylic acid derivatives with pyrrolphenylketone as a key stage. The anxiolytic activity of new substances has been established using open field test with flash. RESULTS: Several synthesized N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamides derivatives significantly increased the total motor activity of Balb/c mice compared to the control. The structureactivity relationship was investigated. The most effective compound was found to be GML-11 (Nbenzyl- N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamide), which had anxiolytic action in the dose range from 0.001 to 0.100 mg/kg (Balb/c, i.p.). This compound is two orders of magnitude higher in dose activity than all other pyrrolo[1,2-a]pyrazine TSPO ligands. CONCLUSION: Molecular modelling methods allowed us to create new TSPO ligands in the series of N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamides with high anxiolytic activity.

Activity of Selected Group of Monoterpenes in Alzheimer's Disease Symptoms in Experimental Model Studies-A Non-Systematic Review.

Alzheimer's disease (AD) is the leading cause of dementia and cognitive function impairment. The multi-faced character of AD requires new drug solutions based on substances that incorporate a wide range of activities. Antioxidants, AChE/BChE inhibitors, BACE1, or anti-amyloid platelet aggregation substances are most desirable because they improve cognition with minimal side effects. Plant secondary metabolites, used in traditional medicine and pharmacy, are promising. Among these are the monoterpenes-low-molecular compounds with anti-inflammatory, antioxidant, enzyme inhibitory, analgesic, sedative, as well as other biological properties. The presented review focuses on the pathophysiology of AD and a selected group of anti-neurodegenerative monoterpenes and monoterpenoids for which possible mechanisms of action have been explained. The main body of the article focuses on monoterpenes that have shown improved memory and learning, anxiolytic and sleep-regulating effects as determined by in vitro and in silico tests-followed by validation in in vivo models.

Enhanced neuroprotective and antidepressant activity of curcumin-loaded nanostructured lipid carriers in lipopolysaccharide-induced depression and anxiety rat model.

The present study aims to develop curcumin-loaded nanostructured lipid carriers (CUR-NLCs) and investigate their neuroprotective effects in lipopolysaccharide (LPS)-induced depression and anxiety model. Nanotemplate engineering technique was used to prepare CUR-NLCs with Compritol 888 ATO and oleic acid as solid and liquid lipid, respectively. Poloxamer 188, Tween 80 and Span 80 were used as stabilizing agents for solid-liquid lipid core. The physicochemical parameters of CUR-NLCs were determined followed by in vitro drug release and in vivo neuroprotective activity in rats. The optimized CUR-NLCs demonstrated nanometric particle size of 147.8 nm, surface charge of -32.8 mV and incorporation efficiency of 91.0%. CUR-NLCs showed initial rapid followed by a sustained drug release reaching up to 73% after 24 h. CUR-NLCs significantly elevated struggling time and decreased immobility time in forced swim and tail suspension tests. A substantial increase in time spent and number of entries into the light and open compartments was observed in light-dark box and elevated plus maze models. CUR-NLCs improved the tissue architecture and suppressed the expression of p-NF-κB, TNF-α and COX-2 in brain tissues from histological and immunohistochemical analysis. CUR-NLCs improved the neuroprotective effect of curcumin and can be used as a potential therapeutics for depression and anxiety.

Anti-depressant, Anxiolytic, and the Muscle Relaxant Activity of Hydroalcoholic Extract of Cissampelos pareira Linn. Leaves.

BACKGROUND: The ethnopharmacological relevance suggests that the ethnic minorities of India use leaves of Cissampelos pareira L. as a traditional medicine for curing various psychopharmacological disorders. OBJECTIVE: To evaluate anti-depressant, anxiolytic, and muscle relaxant activity of hydro-alcoholic extract of Cissampelos pareira. METHODS: Leaves of Cissampelos pareira were extracted using a hydro-alcoholic solvent. The safety of hydro-alcoholic extract of Cissampelos pareira was assessed by acute oral toxicity (OECD 423). The anti-depressant activity was measured using open field test, locomotor test, despair swim test, tail suspension test. The anxiolytic activity was assessed using elevated plus maze and hole board test, and skeletal muscle relaxant activity was assessed using rotarod, grip strength, chimney, and inclined plane test. RESULTS: No moribund status or mortality was observed in experimental mice up to 2000 mg/kg dose of Cissampelos pareira hydro-alcoholic extract (CPHE). In the open field and actophotometer tests, CPHE 200 and 400 mg/kg treated mice significantly abridged ambulation, number of central squares crossed, total locomotion, and depicted less coordinated movements, and in despair swim and tail suspension tests, CPHE 400 mg/kg treated mice significantly decreased duration of immobility and increased number of climbing, confirming its anti-depressant effect. In an elevated plus-maze test, CPHE 200 and 400 mg/kg increased the open arm exploration, while in the hole board test, CPHE 400 mg/kg treated rats augmented the number of head dips, depicting its anxiolytic effect. In rotarod, grip strength, and inclined plane test, CPHE 400 mg/kg treated mice decreased the fall-off time on a rotating rod, suspended wire, or inclined plane. Furthermore, in the chimney test, treatment with CPHE 400 depicted less coordinated movements in mice; the mice of this group took more time to leave the cylinder, depicting its skeletal muscle relaxant effect. CONCLUSION: Based on the results, of this study, it can be concluded that CPHE 400 mg/kg exhibits strong anti-depressant, anxiolytic, and muscle relaxant effects, justifying its traditional uses.

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.

The New Dipeptide TSPO Ligands: Design, Synthesis and Structure-Anxiolytic Activity Relationship.

The translocator protein (TSPO, 18 kDa) plays an important role in the synthesis of neurosteroids by promoting the transport of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting step in neurosteroidogenesis. Stimulation of TSPO by appropriate ligands increases the level of neurosteroids. The present study describes the design, synthesis and investigation of anxiolytic-like effects of a series of N-acyl-tryptophanyl-containing dipeptides. These novel dipeptide TSPO ligands were designed with the original drug-based peptide design strategy using alpidem as non-peptide prototype. The anxiolytic activities were investigated in Balb/C mice using the illuminated open-field and elevated plus-maze tests in outbred laboratory mice ICR (CD-1). Dipeptide GD-102 (N-phenylpropionyl-l-tryptophanyl-l-leucine amide) in the dose range of 0.01-0.5 mg/kg intraperitoneally (i.p.) has a pronounced anxiolytic activity. The anxiolytic effect of GD-102 was abolished by PK11195, a specific TSPO antagonist. The structure-activity relationship study made it possible to identify a pharmacophore fragment for the dipeptide TSPO ligand. It was shown that l,d-diastereomer of GD-102 has no activity, and the d,l-isomer has less pronounced activity. The anxiolytic activity also disappears by replacing the C-amide group with the methyl ester, a free carboxyl group or methylamide. Consecutive replacement of each amino acid residue with glycine showed the importance of each of the amino acid residues in the structure of the ligand. The most active and technologically available compound GD-102, was selected for evaluation as a potential anxiolytic drug.

The Anxiolytic Effect of the Neuropeptide Cycloprolylglycine Is Mediated by AMPA and TrkB Receptors.

Previously we have shown that the neuropeptide cycloprolylglycine is an endogenous positive modulator of AMPA receptors and assumed that the pharmacological effects of CPG are associated with the brain neurotrophic factor. In this paper, we have first demonstrated that DNQX, an inhibitor of AMPA receptors, and K252A, an ihibitor of Trk receptors, prevented the anxiolytic effect of CPG, which confirms the formulated hypothesis.