Potential Anxiolytic Activity Research Articles

Pharmacological evidence of neuro-pharmacological activity of Acacia tortilis leaves in mice.

Acacia tortilis is abundantly present in Saudi Arabia but its neuro-pharmacological activity has not yet been evaluated. In this study, the antidepressant by Forced swim test, Anxiolytic (Light and Dark box) and sedative effects (by using Open Field) of Acacia leaves extract were evaluated in mice. Aqueous extracts of the Acacia tortilis leaves were prepared. Two different doses (400 and 800mg/kg) of the extracts were administered to the mice orally (p.o.). In exploratory behavior, Acacia leave extract (800mg/kg) produced a significant reduction (Veh, 91.00 ± 5.26; Acacia 800mg/kg, 46.33 ± 3.24 p < 0.05) similar to the effect observed with chlorpromazine (CPZ) (Veh, 91.00 ± 5.26; CPZ 1.0mg/kg, 24.20 ± 3.40 p < 0.05). A dose-dependent significant decrease in immobility time was also observed in mice and this effect was comparable to its positive control (Imipramine). However, In light-dark box test, mice treated with high dose (800mg/kg/day) spent significant (p < 0.05) time on the light side of the light-dark box similar to positive control DZP. (Veh, 114.40 ± 6.30s; Acacia 800mg/kg, 162.2 ± 14.9; DZP 1.0mg/kg, 184.20 ± 9.24 p < 0.05). The present research propounded that Acacia tortilis leave extract contains some active ingredients with potential anxiolytic activity at low doses and antidepressant and sedative activity at high doses.

Evaluation of the Anxiolytic and Antidepressant Activities of the Aqueous Extract from Camellia euphlebia Merr. ex Sealy in Mice.

Camellia euphlebia Merr. ex Sealy is a traditional Chinese medicine that has been widely used for improvement of human emotions in the Guangxi Province of southern China. However, there are no studies about the anxiolytic and antidepressant activities of Camellia euphlebia. This study evaluated the anxiolytic and antidepressant activities of the aqueous extract from Camellia euphlebia (CEE) in mice. We found that administration of 400 mg/kg CEE or 20 mg/kg fluoxetine for 7 days significantly reduced the immobility time in both TST and FST. Oral administration of 100 mg/kg extract or 4 mg/kg diazepam for 7 days significantly increased the percentage of time spent and the number of entries into the open arms of the EPMT. In addition, the time spent by mice in the illuminated side of the LDBT was increased. Furthermore, pretreatment with 400 mg/kg CEE for 7 days significantly elevated the level of 5-HT and DA in the whole brain of mice. These results provide support for the potential anxiolytic and antidepressant activity of Camellia euphlebia and contribute towards validation of the traditional use of Camellia euphlebia in the treatment of emotional disorders.

Abstract 1701: A synthetic flavonoid abrogates doxorubicin resistance through inhibition of focal adhesion kinase and P-glycoprotein activity in breast cancer cells

Abstract Chemotherapy is a mainstay in the treatment of breast cancer. FDA approved, Doxorubicin (Dox) is considered to be the most effective chemotherapeutic agent for the treatment of solid tumors like breast cancer. However, resistance to Dox impairs successful treatment. The increased expression of multidrug-resistance P-glycoprotein (P-gp) pump that constantly efflux drugs, such as Dox, is a well documented mechanism of resistance. Flavonoids as a class have been implicated in the inhibition of ABC transporters such as BCRP, P-gp and MRP-1, have potent anxiolytic activity, protect against anthracycline induced cardiotoxicity, and improve general health. Our current study proposes to examine the efficacy of a synthetic flavonoid, SF as a chemotherapeutic agent alone and in combination with Dox in a xenograft nude mouse model and to delineate the specific molecular targets involved. Treatment with a combination of Dox and SF lead to significant cell death in the Dox resistant, MCF-7/Dox cells as compared to treatment with Dox alone. In vivo studies using a xenograft nude mouse model corroborated these findings. Also, mice treated with SF alone and in combination with Dox showed improved overall health. SF also inhibited P-gp pump activity and increased Dox sequestration in cancer cells, leading to chemosensitization. Moreover, SF alone or in combination with Dox caused remarkable de-phosphorylation of constitutively active FAK(Focal Adhesion Kinase) in MCF-7/Dox cells. In conclusion, our study beings forth an excellent prototype candidate, SF- as an anti-tumor agent with little to no toxicity and provides new insights into previously uncharacterized mechanisms for the anti-cancer activity of SF alone and in combination with Dox in resistant breast cancer cells. The desirable traits of endowed pleiotropic activities, safety, synergistic action with therapeutic agents make SF attractive for clinical use. Citation Format: Amrita Datta, Barbara J. Rider, Zakaria Y. Abd Elmageed, Hogyoung Kim, Debasis Mondal, Asim B. Abdel Mageed. A synthetic flavonoid abrogates doxorubicin resistance through inhibition of focal adhesion kinase and P-glycoprotein activity in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1701. doi:10.1158/1538-7445.AM2014-1701

Anti-anxiety activity of Amorphophallus paeoniifolius tuber in mice

ObjectivePrevious studies have shown CNS depressant activity of petroleum ether extract of Amorphophallus paeoniifolius tuber. The current study was devised to explore the anxiolytic activity of petroleum ether extract of A. paeoniifolius tuber in mice, using various animal models of anxiety. MethodsA. paeoniifolius was extracted with petroleum ether by using cold maceration process. The pet ether extract was then tested for its anxiolytic property in mice at different doses (100, 150, 200 mg/kg p.o) using various animal models of anxiety like elevated plus maze, open field test, light & dark test. ResultsThe extract was found to contain steroids, fats & fixed oils. The pet ether extract showed potent anxiolytic activity at a dose dependent manner for elevated plus maze and open field test. The extract however failed to show any significant anxiolytic activity in light and dark test. ConclusionPetroleum ether extract of A. paeoniifolius may act as a potent anxiolytic agent in mice.

Discovery and structure–activity relationship of 1,3-cyclohexyl amide derivatives as novel mGluR5 negative allosteric modulators

A novel series of trans-1,3-cyclohexyl diamides was discovered and characterized as mGluR5 negative allosteric modulators (NAMs) lacking an alkyne moiety. Conformational constraint of one of the amide bonds in the diamide template led to a spirooxazoline template. A representative compound (24d) showed good in vitro potency, high CNS penetration and, upon subcutaneous dosing, demonstrated efficacy in the mouse marble burying test, generally used as indicative of potential anxiolytic activity.

Synthesis of new aryl(hetaryl)-substituted tandospirone analogues with potential anxiolytic activity via reductive Heck type hydroarylations

AbstractTandospirone (I), developed as an anxiolytic drug, is an aryl-piperazine compound that binds to both 5-HT1A and dopamine D4 receptors. Palladium-catalysed hydroarylation reactions of tandospirone analogues containing an oxygen bridge and 3-(trifluoromethyl)phenyl or 2,3-dichlorophenyl groups were studied in order to find a new stereoselective access to a series of new exo-aryl(hetaryl)-substituted derivatives with potential biological activity.

Pharmacological and Toxicological Profile of Extract from Heliopsislongipes and Affinin

Abstract Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics Preclinical Research Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I‐III Regulatory, Quality, Manufacturing Postmarketing Phase IV Heliopsis longipes is a popular medicinal plant in Mexico. One of the main constituents that can be extracted from H. longipes is affinin (N‐isobutylamide). However, available information regarding this compound is scarce, and there is only a single report related to the effect of affinin on the central nervous system. Affinin extracted from H. longipes was evaluated for its psychopharmacological activity in several models and for its safety. H. longipes extract and affinin demonstrated antinociceptive effect, modified anxiety behavior and prolonged the time of sodium pentobarbital‐induced hypnosis. Affinin elicited these activities at high doses. Both the extract and affinin decreased the time of clonic and tonic PTZ‐induced seizures. In the Ames test, neither the extract nor affinin induced mutations in the Salmonella typhimurium strains TA98 and TA100 or TA102 with or without the S9 microsomal fraction. Lethal dose 50 values in mice suggest that the H. longipes extract may contain sedative principles with potential anxiolytic activity; however, it may also increase convulsive activity.

Anticonvulsant and anxiolytic activity of the peptide fraction isolated from the venom of the social wasp Polybia paulista.

Background:Arthropod venoms have attracted interest because they represent a source of neuroactive compounds that can be useful tools in neuroscience and pharmacological investigations.Objective:The purpose of the present work was to evaluate the anticonvulsant, anxiolytic, and behavioral effects of the peptide fraction separated from venom of the social wasp.Materials and Methods:The low- molecular-weight compounds of the venom were separated by ultrafiltration and the bioassays were performed to test anticonvulsant and anxiolytic effects, as well as alterations in the spontaneous behavior of the animals.Results:Intracerebroventricular injections of the compounds induced dose-dependent anticonvulsant effects and a potent anxiolytic activity. Regarding behavioral effects, no significant differences were observed in relation to the saline control group.Conclusion:The low-molecular-weight compounds of the venom of Polybia paulista include neuroactive peptides that can be used as pharmacological resources for anticonvulsant and anxiolytic drug research.

Pharmacological properties of 403U76, a new chemical class of 5-hydroxytryptamine- and noradrenaline-reuptake inhibitor.

403U76 (5-chloro-[[2-[(dimethylamino)methyl]phenyl]thio]benzene- methanol hydrochloride) is a potent, competitive, inhibitor of 5-hydroxytryptamine (5-HT) and noradenaline reuptake into rat brain synaptosomes. Inhibition of 5-HT uptake in-vivo by 403U76 was demonstrated by potentiation of the behavioural effects of 5-hydroxytryptophan in rats and mice and blockade of p-induced depletion of 5-HT in rats. The firing of 5-HT-ergic dorsal raphe neurons in rats was decreased after intravenous administration of low doses of 403U76 as would be predicted for a 5-HT uptake inhibitor. 403U76 antagonized tetrabenazine-induced sedation, an effect associated with inhibitors of noradrenaline uptake, but not with inhibitors of 5-HT uptake. Thus 403U76 affects noradrenergic as well as 5-HT-ergic neurotransmission in-vivo. Potential anxiolytic activity was indicated by reductions in isolation-induced vocalizations in neonates after 403U76 treatment. Low intravenous doses of 403U76 were well tolerated and had no sustained cardiovascular effects. There were no deleterious behavioural side-effects at active doses. Effects observed on isolated tissues or transmitter receptors occurred only at very high concentrations and were pharmacologically unimportant. Thus 403U76 can be considered a potential antidepressant/anxiolytic agent that is a potent, selective inhibitor of 5-HT and noradrenaline reuptake.

Prise en charge médicamenteuse de l’anxiété chez le patient souffrant de schizophrénie

Anxiety is a major and frequent symptom of schizophrenia, which is associated with an increased risk of relapse, impaired functioning, lower quality of life and increased incidence of suicide attempts. Despite its clinical relevance, anxiety in schizophrenia remains poorly understood. In the prodromic phase, anxiety indicates a progression towards psychotic decompensation. After a first episode, it is an indicator of relapse. Two approaches have been used to investigate anxiety in schizophrenia: (i) categorical approach (comorbidity of schizophrenia and anxiety disorders) and (ii) dimensional approach (anxiety as a major symptom of the "dysphoric" dimension). Clinical categorical studies reported an increased frequency of comorbidity between schizophrenia and obsessive-compulsive disorder, panic disorder, social phobia, post-traumatic stress disorder, generalized anxiety disorder, agoraphobia, and specific phobia. The dimensional approach proposes that five different factors contribute to the structure of the Positive and Negative Syndrome Scale (PANSS), with anxiety as a major symptom of the "dysphoria" dimension. Concerning diagnosis, it is unclear whether psychotic and neurotic anxiety differs in nature or intensity. Nevertheless, both are frequently opposed. Psychotic anxiety is intense, profound and hermetic. In contrast to neurotic anxiety, it is associated with psychomotor disturbances, such as agitation and sideration. There is no specific tool to evaluate anxiety in schizophrenia. The dimensional approach usually runs an evaluation using items or factors extracted from the most widely-used scales, i.e. PANSS or Brief Psychiatric Rating Scale (BPRS) or from anxiety scales developed in non-schizophrenic populations, such as the Hamilton Anxiety Scale (HAMA). Recently, we developed a specific scale for hetero-evaluation (Échelle Anxiété Schizophrénie [EAS scale]). The EAS scale was recently validated and the study of its sensitivity is ongoing. THERAPEUTICAL ISSUES: Several studies have examined the effects of antipsychotics on the anxious/depressive cluster extracted from the PANSS, and some other studies have specifically evaluated the effect of antipsychotics on depressive symptoms using the Montgomery and Asberg Depression Rating Scale (MADRS) and Calgary Depression Scale for Schizophrenia (CDSS), but to our knowledge, no study has reported the effect of antipsychotics or other treatment on anxiety when using a schizophrenia-specific scale. There are no specific guideline treatments for anxiety in schizophrenia. Among phenothiazines, cyamemazine is frequently prescribed in France, because of its potent anxiolytic activity and good neurological tolerance. Some authors have suggested a specific treatment with benzodiazepines. However, benzodiazepines should be used with caution, due to undesirable actions such as dependence, rebound and potentiation of certain lateral effects.

ChemInform Abstract: Synthesis and Evaluation of a Series of Aryl(e)fused Pyrazolo(4,3-c) pyridines with Potential Anxiolytic Activity.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Anxiolytic properties of a 2-phenylindolglyoxylamide TSPO ligand: Stimulation of in vitro neurosteroid production affecting GABA A receptor activity

A number of neurosteroids have been demonstrated to exert anxiolytic properties by means of a positive modulation of inhibitory GABAergic neurotransmission. The observation that neurosteroid synthesis can be pharmacologically regulated by ligands to the mitochondrial translocator protein (TSPO) has prompted the search for new, more selective TSPO ligands able to stimulate steroidogenesis with great efficacy. In the present study, the potential anxiolytic activity of a selective TSPO ligand, N,N-di-n-propyl-2-(4-methylphenyl)indol-3-ylglyoxylamide (MPIGA), was tested by means of the elevated plus maze paradigm. Moreover, the in vitro effects on synaptoneurosomal GABA(A) receptor (GABA(A)R) activity exerted by the conditioned salt medium from MPIGA-treated ADF human glial cells were investigated. MPIGA (30mg/kg) was found to affect rats' performance in the elevated plus maze test significantly, leading to an increase in both entries and time spent in the open arms. This same dose of MPIGA had no effect on rats' spontaneous exploratory activity. The conditioned salt medium from MPIGA-treated ADF cells potentiated the (36)Cl(-) uptake into cerebral cortical synaptoneurosomes. The exposure of ADF cells to MPIGA stimulated the production of pregnelonone derivatives including allopregnanolone, one of the major positive GABA(A)R allosteric modulator. In conclusion, the TSPO ligand MPIGA is a promising anxiolytic drug. The mechanism of action by which MPIGA exerts its anxiolytic activity was identified in the stimulation of endogenous neurosteroid production, which in turn determined a positive modulation of GABA(A)R activity, thus opening the way to the potential use of this TSPO ligand in anxiety and depressive disorders.

Pharmacological characterization of MP349, a novel 5-HT1A-receptor antagonist with anxiolytic-like activity, in mice and rats.

The purpose of this study was to further characterize the pharmacological effects of MP349 (trans-1-(2-methoxyphenyl)-4-(4-succinimidocyclohexyl)piperazine), a new serotonin 5-HT(1A) postsynaptic receptor antagonist, using several biochemical and behavioural assays. The silent 5-HT(1A)-receptor antagonist WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide) was used as a reference compound in in-vivo tests, and diazepam served as standard anxiolytic drug in animal models of anxiety. In this study we showed that MP349 bound with moderate affinity (K(i) = 234 nM) for alpha(1)-adrenoceptors, and with very low affinity (K(i) > 2600 nM) for 5-HT(2A), dopamine D(1), D(2) and benzodiazepine receptors. The effects of MP349 on presynaptic 5-HT(1A) receptors were studied in two models (mice and rats). Like WAY 100635, MP349 antagonized the hypothermia induced by the 5-HT(1A)-receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin(8-OH-DPAT) in mice. Neither MP349 nor WAY 100635 administered alone induced hypothermia. In a rat microdialysis study, MP349 (like WAY 100635) did not affect 5-HT dialysate level in the prefrontal cortex; however, when given before 8-OH-DPAT, it inhibited the decrease in 5-HT release induced by the 5-HT(1A )agonist. The data demonstrated that MP349 behaved like a functional antagonist of presynaptic 5-HT(1A) receptors. The potential anxiolytic activity of MP349 and reference drugs was examined in a conflict drinking test in rats, a plus-maze test in rats and a four-plate test in mice. MP349 and WAY 100635 produced anxiolytic-like effects, though somewhat weaker than those induced by diazepam, and only in the case of diazepam the anxiolytic-like effects were dose-dependent. Moreover, MP349 administered in doses inducing anxiolytic-like effects did not disturb the locomotor activity (open field test) or locomotor coordination (rota-rod test) of rats. These and earlier results indicated that MP349 was an antagonist of 5-HT(1A) receptors which exhibited anxiolytic-like activity in an animal model of anxiety.

First Evidence for an Anxiolytic Effect of a Diterpenoid from Salvia Cinnabarina

The potential anxiolytic and anti-depressive activity of CMP1 was studied in the elevated plus-maze test and in the forced swimming test. Furthermore, CMP1 sedative activity was evaluated in pentobarbital treated animals; the effect of CMP1 on spontaneous motor activity (total locomotion) was also evaluated. Our data show that CMP1, at doses that did not affect locomotion, was able to induce anxiolytic and sedative, but not anti-depressive effects. In conclusion, our results represent first evidence for an anxiolytic activity of this diterpenoid from Salvia cinnabarina.

P.4.d.001 BNC210 is a novel, fast acting compound with potent anxiolytic activity and no side effects

P.4.d.001 BNC210 is a novel, fast acting compound with potent anxiolytic activity and no side effects

Evaluation of anxiolytic activity of spray dried powders of two South Brazilian Passiflora species

The Passiflora extracts have been used in folk medicine because of its reputed sedative and anxiolytic properties. The present study aimed to compare the potential anxiolytic activity of two Passiflora spray-dried powders obtained from P. alata and P. edulis, known in Brazil as 'maracujá'. Male adult Swiss rats were treated with 200, 400 and 800 mg/kg of spray-dried powders p.o. and anxiolytic activity was evaluated using the elevated plus-maze test. The spray-dried powders showed anxiolytic activity in doses of 400 and 800 mg/kg. Our results support the potential anxiolytic effect of Passiflora spray-dried powders (P. alata and P. edulis).

Preclinical pharmacology of F-98214-TA, a novel potent serotonin and norepinephrine uptake inhibitor with antidepressant and anxiolytic properties

Serotonin (5-HT) and norepinephrine (NE) re-uptake inhibitors (SNRIs) have been proposed to have a higher efficacy and/or faster onset of action than previously available antidepressants. We examined in biochemical, electrophysiological and behavioural assays the antidepressant properties of (S)-(-)-4-[(3-fluorophenoxy)-phenyl]methyl-piperidine (F-98214-TA), a compound that displays very high affinity for 5-HT and NE transporters. F-98214-TA potently inhibited the uptake of both 5-HT and NE into rat brain synaptosomes (IC50 = 1.9 and 11.2 nM, respectively) and decreased the electrical activity of dorsal raphe serotonergic neurones (ED50 = 530.3 microg/kg i.v.), an effect completely abolished by the 5-HT(1A) antagonist WAY100,635. In acute behavioural assays in mice, the orally administered compound potentiated the 5-hydroxy-tryptophan (5-HTP)-induced syndrome [minimal effective dose (MED) = 10 mg/kg], antagonized the hypothermia induced by a high dose of apomorphine (ED50 = 2 mg/kg) and reduced the immobility in the tail suspension test (MED = 10 mg/kg). Moreover, it also decreased the immobility in the forced swimming test in mice and rats (30 mg/kg, p.o.). Chronic administration of F-98214-TA (14 days, 30 mg kg(-1) day(-1), p.o.) attenuated the hyperactivity induced by olfactory bulbectomy in rats, confirming its antidepressant-like properties. Interestingly, the same dosage regimen significantly increased the social interaction time in rats, suggesting an additional potential anxiolytic activity. In most assays the compound was more potent than fluoxetine, venlafaxine and desipramine. F-98214-TA is a novel SNRI that displays greater potency than other reference antidepressants in animal models predictive of antidepressant and anxiolytic activities.

Synthesis of new N-substituted cyclic imides with an expected anxiolytic activity. XVII. Derivatives of 1-ethoxybicyclo[2.2.2]-oct-5-one-2,3-dicarboximide

The preparation of a number of derivatives of 1-ethoxybicyclo[2.2.2]-oct-5-one-2,3-dicarboximide with potential anxiolytic activity has been described. The aim of our study was to obtain new analogs of tandospirone.

Anxiolytic properties of botanical extracts in the chick social separation-stress procedure.

The recent growth in sales of natural products labeled as dietary supplements in the United States has renewed scientific interest in the study of the therapeutic effects of multi-component botanical products. This study sought to determine whether botanical extracts derived from the Rutaceae family, Acori graminei, the Magnoliaceae family, Alchemilla vulgaris and Primula veris, which had previously been identified in bioassays as having potential anxiolytic activity, were active in the chick social separation-stress procedure. Eight-day-old chicks received IP injections of test articles 30 min before being tested in the presence of two social companions or in isolation for a 3-min observation period. Dependent measures were: a) latency to adopt a ventral recumbent posture to index sedation, b) number of vocalizations to index separation-distress and c) a composite pain score (comprised of footlift frequency and footlift duration in response to 50 microl of 0.10% formalin injected into the plantar surface of the foot) to index stress-induced analgesia. Proprietal extracts NPS00033 from the Rutaceae plant family and NPS00039 (Relora) from the Magnoliaceae plant family screened positive in this chick model without causing sedation. These results suggest that botanical extracts Relora and NPS00033 may be useful in modulating anxiety states.

Evidence That Total Extract of Hypericum perforatum Affects Exploratory Behavior and Exerts Anxiolytic Effects in Rats

Clinical trials have extensively reported the ability of Hypericum perforatum extracts to exert a significant antidepressant activity. Hypericin, the main constituent of H. perforatum extract, is no more regarded as the active principle of the antidepressant activity of the drug. Hence, the question of which constituents are involved in the basic activity of the total extract, is still waiting for an answer. In the present study we focused our attention on the potential anxiolytic activity of H. perforatum total extract, and of some pure components such as protohypericin and a fraction containing hypericin and pseudohypericin. Herein we report that the total extract of H. perforatum increases the locomotor activity in the open field and exerts anxiolytic activity in the light–dark test, whereas the single components did not show any effect. Interestingly, the anxiolytic activity of the total extract was blocked by pretreatment of rats with the benzodiazepine antagonist Flumazenil, hence suggesting an implication of benzodiazepine receptor activation in the anxiolytic effect of H. perforatum extract. Electrophysiological studies, performed to gain more information on the mechanism of action, showed that hypericin reduced the GABA-activated chloride currents, while pseudohypericin did an opposite effect. Furthermore, both hypericin and pseudohypericin inhibited the activation of NMDA receptors.