Anxiolytic-like Activity Research Articles

Attaining in vivo selectivity of positive modulation of α3βγ2 GABAA receptors in rats: A hard task!

It is unclear whether GABAA receptors (GABAARs) that contain the α3-subunit are substantially involved in the anxiolytic effects of benzodiazepines (BDZs). In the present study, we tested YT-III-31, a newer BDZ ligand with functional preference for α3βγ2 GABAARs, in two paradigms of unconditioned anxiety, the open field and elevated plus maze in rats. The effective dose of YT-III-31 (2 mg/kg) displayed a clear anxiolytic-like profile, unhampered by sedative action, in both tests. At a higher dose (10 mg/kg), YT-III-31 induced ataxia in the rotarod and sedation in spontaneous locomotor activity test. The latter effect was preventable by flumazenil and βCCt, the non-selective and α1βγ2 GABAAR affinity-selective antagonist, respectively, demonstrating that sedative properties of YT-III-31, when attained, are mediated by the α1γ2 site. To elucidate the receptor substrate of subtle behavioral differences between YT-III-31 and diazepam, we approximated in vivo receptor potentiation for both ligands, based on estimated unbound concentrations in rat brains. Far different from diazepam, YT-III-31 has significantly lower affinity for the α1γ2 over other BDZ-sensitive sites, and at lower doses (1–2 mg/kg) was devoid of potentiation at α1βγ2 GABAARs. The approximation approach revealed a modest selectivity of YT-III-31 for α3γ2- in comparison to α2γ2 and α5γ2 binding sites, suggesting that its anxiolytic-like activity may not necessarily or predominantly reflect potentiation at α3βγ2 GABAARs. Nonetheless, as the anxiolytic effects are achievable at a dose devoid of any sedative potential, and having favorable safety (cytotoxicity) and metabolic stability profile, YT-III-31 represents a valuable candidate for further translational research.

The anxiolytic-like effects of ginsenoside Rg3 on chronic unpredictable stress in rats

The present study is to evaluate the anxiolytic-like activities underlying ginsenoside Rg3 (GRg3). The anxiolytic-like activities were induced by GRg3 (20 and 40 mg/kg, i.g), evidenced by blocking the decreased time and entries in the open arms in elevated plus maze test and by reversing the increased latency to feed in novelty-suppressed feeding test. In addition, the decreased levels on progesterone, allopregnanolone, serotonin (5-HT) in the prefrontal cortex and hippocampus of chronic unpredictable stress (CUS) were blocked by GRg3 (20 and 40 mg/kg, i.g). Furthermore, the increased corticotropin releasing hormone, corticosterone and adrenocorticotropic hormone were blocked by GRg3 (20 and 40 mg/kg, i.g). Collectively, the anxiolytic-like effects produced by GRg3 were associated with the normalization of neurosteroids biosynthesis, serotonergic system as well as HPA axis dysfunction.

Synthesis and activity of di- or trisubstituted N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives on the central nervous system

Aim of the study was evaluation of anxiolytic, antidepressant, anticonvulsant and analgesic activity in a series of a consistent group of compounds. A series of eleven new N-(phenoxyalkyl)- or N-{2-[2-(phenoxy)ethoxy]ethyl}piperazine derivatives has been obtained. Their affinity towards 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, D2 and α1 receptors has been assessed, and then functional assays were performed. The compounds were evaluated in mice, i.p. for their antidepressant-like (forced swim test), locomotor, anxiolytic-like (four-plate test) activities as well as – at higher doses – for anticonvulsant potential (MES) and neurotoxicity (rotarod). Two compounds (3, 6) were also evaluated for their analgesic activity in neuropathic pain models (streptozocin test, oxaliplatin test) and they were found active against allodynia in diabetic neuropathic pain at 30 mg/kg. Among the compounds, anxiolytic-like, anticonvulsant or analgesic activity was observed but antidepressant-like activity was not. One of the two most interesting compounds is 1-{2-[2-(2,4,6-trimethylphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazine dihydrochloride (9), exhibiting anxiolytic and anticonvulsant activity in mice, i.p. 30 min after administration (at 2.5 mg/kg and ED50 = 26.33 mg/kg, respectively), which can be justified by the receptor profile: 5-HT1A Ki = 5 nM (antagonist), 5-HT7 Ki = 70 nM, α1 Ki = 15 nM, D2 Ki = 189 nM (antagonist). Another interesting compound is 1-[3-(2,4,6-trimethylphenoxy)propyl]-4-(4-methoxyphenyl)piperazine dihydrochloride (3), exhibiting anxiolytic, anticonvulsant and antiallodynic activity in mice, i.p., 30 min after administration (at 10 mg/kg, ED50 = 23.50 mg/kg, at 30 mg/kg, respectively), which can be related with 5-HT1A weak antagonism (Ki = 146 nM), or other possible mechanism of action, not evaluated within presented study. Additionally, for the most active compound in the four-plate test (7), molecular modeling was performed (docking to receptors 5-HT1A, 5-HT2A, 5-HT7, D2 and α1A).

Isolation and Characterization of Two New Secondary Metabolites From Quercus incana and Their Antidepressant- and Anxiolytic-Like Potential.

The ethyl acetate fraction of Quercus incana yielded two new compounds [1 and 2]. The characterization and structure elucidation of these compounds were carried out through various spectroscopic techniques such as mass spectrometry along with one- and two-dimensional NMR techniques. The structural formula was deduced to be 2-(4-hydroxybutan-2-yl)-5-methoxyphenol [1] and 4-hydroxy-3-(hydroxymethyl) pentanoic acid [2]. The elevated plus maze (EPM) and light–dark box (LDB) tests (classical mouse models) were performed in order to reveal the anxiolytic potential of both compounds [1 and 2]. Both compounds displayed dose-dependent increases in open-arm entries and time spent in open arms in EPM (∗P < 0.05, ∗∗P < 0.01), and increased the time spent in the lit compartment and increased transitions between the two compartments in LDB test (∗P < 0.05, ∗∗P < 0.01). Co-administration of selective benzodiazepine (BZP) receptor antagonist, flumazenil (2.5 mg/kg) with compounds [1 and 2] decreased the anxiolytic-like activity of both compounds in the EPM indicating BZP-binding site of GABA-A receptors are involved in the anxiolytic-like effect. Similarly, both compounds at the dose level of 10 and 30 mg/kg, i.p. exerted pronounced antidepressant-like effect in both forced swimming as well as tail suspension tests (∗P < 0.05, ∗∗P < 0.01; ANOVA followed by Dunnett’s post hoc test). The effect at 30 mg/kg was comparable to the reference drug imipramine (60 mg/kg).

Evaluation of the Neurobehavioral Properties of Naringin in Swiss Mice.

This study was carried out to investigate the neurobehavioral properties of naringin, a flavonoid compound formed from naringenin on behavioral models in mice. The neurobehavioral property of naringin (2.5, 5 and 10 mg/kg) administered intraperitoneally (i.p.) was assessed on novelty-induced rearing, locomotor behavior using open field test; anxiolytic effect was evaluated using hole-board, light and dark box, and elevated-plus maze paradigms. The anti-depressant-like property was also assessed using forced swim test (FST), tail suspension test (TST) and social interaction test (SIT). The cognitive enhancing effect of naringin was evaluated using Y-maze test. Intraperitoneal administration of naringin (2.5 and 5 mg/kg) demonstrated significant (p<0.05) increase in rearing behavior but not the spontaneous motor activity in comparison to control. In the anti-depressant test, naringin (2.5, 5 and 10 mg/kg, i.p.) significantly decreased the duration of immobility in the FST and TST, and increased the % social interaction preference in the SIT relative to controls, suggesting anti-depressant-like and increased social behaviors. Moreover, naringin also exhibited anxiolytic and memory enhancing properties in mice. These findings suggest that naringin possesses anti-depressant- and anxiolytic-like activities as well as memory enhancing effect in mice.

Neuropharmacological and molecular docking studies of xanthones from Swertia corymbosa

Anxiety represents a public health problem consistently found to be the most prevalent class of mental disorders among people of all ages. Xanthones possess many biological properties, including neuroprotective, antioxidant or antidepressant-like. In this study, we aimed to investigate anxiolytic-like antidepressant and anticonvulsant properties of isolated xanthones from Swertia corymbosa. We evaluated anxiolytic-like activity of compounds 1–3 in the mouse elevated plus maze (EPM) and open field test (OF). We examined the influence on locomotor activity in mouse to determine if the effect observed in the actophotometer specific. We used step-through rotarod tests to evaluate the motor function and muscle grip. Compounds 1–3 significantly induced an increase in the number of entries into open arms and a decrease in time spent into closed arms at the dose of 50 mg/kg body weight (BW). The compounds also induced increase of rearing and decrease grooming at the doses of 25 and 50 mg/kg BW during the OF test. In addition, compounds induced a significant increase of time taken to enter at the center of the experimental set at the dose of 50 mg/kg BW during the open field test. The compounds 1–3 significantly delayed the onset as well as decreased the pentylenetetrazole and isoniazid-induced seizure tests. Compound 3 pretreatment significantly improved survivals in pentylenetetrazole and isoniazid-induced seizure tests. In silico studies reveal its possible mechanism of action shed on light to develop novel drugs against CNS disorders.

P.2.001 - Rapid anxiolytic effects of a serotonin type 4 receptor agonist involve prefrontal cortex/brainstem neural circuit recruitment

Anxiety disorders are one of the most prevalent mental health conditions. Although benzodiazepines are very effective in reducing acute anxiety, their adverse effects limit their use chronically. Selective serotonin reuptake inhibitors (SSRIs) are considered to be the first line of therapy for anxiety disorders but their delayed onset of action emphasizes the need for faster acting drugs [1]. Recently, it has been suggested that 5-HT4 receptor (5-HT4R) may bring new hope for treating anxiety/depression symptoms [2]. This study aimed to assess whether acute 5-HT4R activation could induce fast-anxiolytic-like effects, using an anxious mouse strain. Thus, male BALB/cJRJ mice were administered intraperitoneally 45min before testing (open field, OF; elevated plus maze, EPM; novelty suppressed feeding, NSF) with a single dose of saline, fluoxetine (SSRI, 18 mg/kg), diazepam (benzodiazepine, 1.5 mg/kg) or RS67333 (5-HT4R agonist, 1.5 mg/kg). A one-way ANOVA followed by Fisher’s PLSD post-hoc test showed that, unlike fluoxetine, but similarly to diazepam, acute systemic RS67333 administration produced fast anxiolytic-like effect in all tested paradigms (i.e., +62% and +66% increase in time spent respectively in center in the OF and in the open arms in EPM and +63% reduce latency to feed in the NSF compared to vehicle, all p In addition, since the 5-HT4R is mainly expressed in the medial prefrontal cortex (mPFC) [3], we tested whether mPFC local injection, of RS6733 could mimic the anxiolytic effect of a systemic injection. Thus, a single dose of RS67333 (0.5 µg/side) administered in the mPFC 45 minutes prior testing showed comparable anxiolytic-like activity than that of the systemic diazepam (1.5 mg/kg) administration in the EPM and the NSF (i.e., + 77% increase in time spent in the open arms in the EPM compared to vehicle, all p Finally, we explored whether mPFC pyramidal cell projections-targeting to the dorsal raphe nucleus (DRN) circuit [4] is involved in RS67333 induced-anxiolytic-like activity. Interestingly, an acute mPFC injection of RS67333 and diazepam (1.5 µg/side) induced-fast anxiolytic-like effects was abolished in serotonin-pCPA depleted mice (-86% in the 5-HT content in the PFC of control mice) as compared to vehicle-treated mice (respectively, -78% and -73% less time spent in open arms in the EPM than vehicle-treated mice, all p In conclusion, our study demonstrated that (i) acute 5-HT4R activation induced fast anxiolytic-like effects in anxious stressed mice similar to benzodiazepine, (ii) the mPFC-DRN circuit contribute to the fast anxiolytic-like activity of RS67333 and diazepam and (iii) despite different pharmacological targets, 5-HT4R agonist and benzodiazepine, share common neural circuit recruitment to induced fast anxiolytic-like effect. Therefore, we envision that the 5-HT4R may represent an innovative and rapid onset therapeutic approach to treat anxiety disorders.

Polymethoxyflavones from Nicotiana plumbaginifolia (Solanaceae) Exert Antinociceptive and Neuropharmacological Effects in Mice.

Polymethoxylavones (PMFs) are known to exhibit significant anti-inflammatory and neuroprotective properties. Nicotiana plumbaginifolia, an annual Bangladeshi herb, is rich in polymethoxyflavones that possess significant analgesic and anxiolytic activities. The present study aimed to determine the antinociceptive and neuropharmacological activities of polyoxygenated flavonoids namely- 3,3′,5,6,7,8-hexamethoxy-4′,5′-methylenedioxyflavone (1), 3,3′,4′,5′,5,6,7,8-octamethoxyflavone (exoticin) (2), 6,7,4′,5′-dimethylenedioxy-3,5,3′-trimethoxyflavone (3), and 3,3′,4′,5,5′,8-hexamethoxy-6,7-methylenedioxyflavone (4), isolated and identified from N. plumbaginifolia. Antinociceptive activity was assessed using the acetic-acid induced writhing, hot plate, tail immersion, formalin and carrageenan-induced paw edema tests, whereas neuropharmacological effects were evaluated in the hole cross, open field and elevated plus maze test. Oral treatment of compounds 1, 3, and 4 (12.5–25 mg/kg b.w.) exhibited dose-dependent and significant (p < 0.01) antinociceptive activity in the acetic-acid, formalin, carrageenan, and thermal (hot plate)-induced pain models. The association of ATP-sensitive K+ channel and opioid systems in their antinociceptive effect was obvious from the antagonist effect of glibenclamide and naloxone, respectively. These findings suggested central and peripheral antinociceptive activities of the compounds. Compound 1, 3, and 4 (12.5 mg/kg b.w.) demonstrated significant (p < 0.05) anxiolytic-like activity in the elevated plus-maze test, while the involvement of GABAA receptor in the action of compound 3 and 4 was evident from the reversal effects of flumazenil. In addition, compounds 1 and 4 (12.5–25 mg/kg b.w) exhibited anxiolytic activity without altering the locomotor responses. The present study suggested that the polymethoxyflavones (1–4) from N. Plumbaginifolia could be considered as suitable candidates for the development of analgesic and anxiolytic agents.

MF-8, a novel promising arylpiperazine-hydantoin based 5-HT7 receptor antagonist: In vitro drug-likeness studies and in vivo pharmacological evaluation

We report the in vitro drug-likeness studies and in vivo pharmacological evaluation for a new potent 5-HT7 receptor antagonist MF-8 (5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylhydantoin). The in vitro tests showed good permeability, very good metabolic stability, low risk of drug-drug interactions and satisfying safety profile. Moreover, MF-8 showed excellent antidepressant-like activity in the forced swim test in rodents and promising anxiolytic-like activity in the four-plate test in mice. Regarding the potent affinity, high selectivity and antagonistic activity of MF-8 for the 5-HT7 receptor as well as excellent drug – like properties in vitro and confirmed in vivo pharmacological activity, MF-8 should be considered as a very significant molecule in the search for a new class of anti-depressant drugs.

Triethylene glycol-like effects of Ashwagandha (Withania somnifera (L.) Dunal) root extract devoid of withanolides in stressed mice.

Background:The objective of the study is to compare stress resistance-promoting effect of triethylene glycol (TEG) and root extract of Ashwagandha (Withania somnifera) i.e. withanolide-free root extract of Withania somnifera (WFWS).Materials and Methods:Mice groups treated orally with 10 mg/kg TEG or WFWS (3.3, 10, 33.3, or 100 mg/kg) for 12 consecutive days were subjected to foot shock stress-triggered hyperthermia test on the 1st, 5th, 7th and 10th day and to marble-burying test on the following 2 days. Effects of treatment on stress-triggered alteration in body weight, core temperature, blood glucose, insulin and cortisol level were quantified and statistically analyzed.Results:WFWS doses up to 10 mg/kg/day were as effective as TEG in affording protection against stress-triggered alteration in body weight, core temperature and marble-burying behavior. Protection against stress-triggered alteration in blood glucose and insulin level, as well as antidepressants or anxiolytic-like activities in the behavioral test, were observed in the higher two WFWS doses (33.3 and 100 mg/kg) treated groups only.Conclusion:Ashwagandha metabolites other than withanolides contribute to its stress resistance increasing effects. The observations suggest that modulation of physiological functions of gut microbiota may be involved in the mode of action of Withania somnifera root extracts.

A new piperazine derivative: 1-(4-(3,5-di-tert-butyl-4-hydroxybenzyl) piperazin-1-yl)-2-methoxyethan-1-one with antioxidant and central activity.

In the scope of a research program aimed at developing new drugs for the treatment of central nervous system diseases, we describe herein the synthesis and pharmacological evaluation of 1-(4-(3,5-di-tert-butyl-4-hydroxybenzyl) piperazin-1-yl)-2-methoxyethan-1-one (LQFM180). This compound showed antioxidant activity in two models, electroanalytical assays, and DPPH activity. Moreover, in behavioral tests as the open field test LQFM180 (9.4, 18.8, and 37.6mg/kg, per oral (p.o.)), we detected anxiolytic-like activity. In the sodium pentobarbital-induced sleep test, LQFM180, in all doses, decreased the latency to sleep and increased sleep duration, indicating central depressant activity; moreover, in the chimney test, LQFM180 did not alter motor activity. LQFM180 (18.8mg/kg, p.o.) increased the time and number of entries on open arms in the elevated plus maze test, suggesting anxiolytic-like activity, which was reversed by NAN-190 and p-chlorophenylalanine, indicating a role of the serotonergic pathway on this effect. In the forced swimming test, LFQM180 (18.8mg/kg, p.o.) decreased immobility time, suggesting antidepressant-like activity, which was reversed by monoaminergic antagonists, indicating a role for the serotonergic, noradrenergic, and dopaminergic pathways. Competition binding assays showed that LQFM180 was able to bind to the α1B, 5-HT1A, and D2 receptors, however, within the low micromolar range. We conclude that LQFM180 should be considered as a scaffold for drug candidate development.

Effects of a hydroethanolic extract of Boophone disticha bulb on anxiety-related behaviour in naive BALB/c mice

Ethnopharmacological relevanceBoophone disticha is one of the most important medicinal bulbs of Southern Africa. Previous in vitro studies have shown that it's crude ethanolic extracts and some alkaloidal phytoconstituents possesses high affinity for the serotonin transporter protein (SERT) and serotonin receptor 1a (5HT1a) which are both implicated in the pathogenesis and treatment of anxiety disorders. However, there are no in vivo studies that validates the anxiolytic actions of the plant. Aim of the studyThis study was therefore set to determine the anxiolytic-like activity of an orally administered hydroethanolic extract of B. disticha bulbs in naive mice using the behavioural tests of anxiety. Materials and methodsNaïve adult male BALB/c mice were randomly placed into five treatment groups (n=6–10): vehicle control (10ml/kg 0.9% NaCl), positive control (1mg/kg diazepam) and the hydroethanolic extract of B. disticha (10, 25 and 40mg/kg p.o.). Souk test, elevared plus maze and open field tests were used to evaluate the anxiolytic-like activity of the B. disticha extract. ResultsDiazepam-treated mice exhibited higher number of sector visits and line crossings in the ST, rearings in the OF and head dips in the EPM than the control (p<0.05). B. disticha extract treated groups expressed higher sector visits at 10mg/kg, and, unprotected head dips at 25mg/kg in the ST, as well as, open arm time entries at 10mg/kg dose, and unprotected head dips at all doses in the EPM than the control group (p<0.05). The 25mg/kg B. disticha dose group exhibited highest anxiolytic-like activity in both the ST and OF, while the 10mg/kg was most active in the EPM. ConclusionThe extract of B. disticha exerted good anxiolytic-like activity in both the ST and OF at medium dose (25mg/kg), while the low dose (10mg/kg) showed prominent anxiolytic-like activity in the EPM.

N-propyl-2,2-diphenyl-2-hydroxyacetamide, a novel α-hydroxyamide with anticonvulsant, anxiolytic and antidepressant-like effects that inhibits voltage-gated sodium channels

In patients with epilepsy, anxiety and depression are the most frequent psychiatric comorbidities but they often remain unrecognized and untreated.We report herein the antidepressant-like activity in two animal models, tail suspension and forced swimming tests, of six anticonvulsants α-hydroxyamides. From these, N-propyl-2,2-diphenyl-2-hydroxyacetamide (compound 5) emerged not only as the most active as anticonvulsant (ED50 = 2.5mg/kg, MES test), but it showed the most remarkable antidepressant-like effect in the tail suspension and forced swimming tests (0.3–30mg/kg, i.p.); and, also, anxiolytic-like action in the plus maze test (3–10mg/kg, i.p.) in mice. Studies of its mechanism of action, by means of its capacity to act via the GABAA receptor ([3H]-flunitrazepam binding assay); the 5-HT1A receptor ([3H]-8-OH-DPAT binding assay) and the voltage-gated sodium channels (either using the patch clamp technique in hNav 1.2 expressed in HEK293 cell line or using veratrine, in vivo) were attempted. The results demonstrated that its effects are not likely related to 5-HT1A or GABAAergic receptors and that its anticonvulsant and antidepressant-like effect could be due to its voltage-gated sodium channel blocking properties.

Mapping in mice the brain regions involved in the anxiolytic-like properties of α-casozepine, a tryptic peptide derived from bovine αs1-casein

α-Casozepine, a bioactive peptide from milk casein, displays an anxiolytic-like activity in many species. Since its mode of action is still not elucidated, a study was conducted in Swiss mice to investigate c-Fos expression, a marker of neuronal activity, in different brain areas. After an intraperitoneal injection of α-casozepine (1mg/kg), animals were placed either in a non-stressful or in an anxiety-inducing situation triggered with a light/dark box. No effect of α-casozepine on c-Fos expression was observed in the non-stressful situation. In the stressful situation, modulation of neuronal activity by α-casozepine was observed in different brain regions compared to that of vehicle. However, while diazepam, a benzodiazepine, modulated neuronal activity the same way in hippocampus, accumbens nucleus and hypothalamus, differences were observed in c-Fos expression in amygdala and prefrontal cortex compared to α-casozepine. These results strengthen the assumption that the anxiolytic mechanisms of α-casozepine differ partly of those of diazepam.

Antinociceptive, anti-inflammatory and anxiolytic-like effects of the ethanolic extract, fractions and Hibalactone isolated from Hydrocotyle umbellata L. (Acariçoba) – Araliaceae

Hydrocotyle umbellata Linn. (Araliaceae) is specie used in the treatment of inflammatory diseases. Crude extract (E-HU) was prepared from H. umbellata subterraneous parts and fractionated by liquid-liquid partition, resulting hexane fraction (HF-HU), dichloromethane fraction (DF-HU), ethyl acetate fraction (EAF-HU) and aqueous fraction (AF-HU). The hibalactone (HU-1) was isolated from the DF-HU and its structure was elucidated by 1H NMR and 13C NMR Spectroscopy, mass spectrometry and crystallographic x-ray analysis. The formalin-induced nociception was used to evaluate antinociceptive activity; carrageenan-induced edema and pleurisy tests to evaluate anti-inflammatory activity and light-dark box to evaluate anxiolytic-like activity in mice. The acute oral treatments with E-HU (1000mg/kg), DF-HU (150mg/kg), EAF-HU (400mg/kg) and HU-1 (33mg/kg) decreased the licking time in both phases of the formalin test. In the carrageenan-induced inflammation models, the treatment with the same doses of E-HU, DF-HU, EAF-HU and HU-1 reduced the paw edema formation and leukocytes account into pleural cavity. In silico findings suggest that hibalactone present anti-inflammatory activity by interacting with the enzymes 5-lipoxygenase and cyclooxygenase-2. In the light dark box, the treatments with DF-HU, EAF-HU and HU-1 revealed an anxiolytic like effect. Thus, the E-HU and fractions of H. umbellata showed antinociceptive, anti-inflammatory and anxiolytic like activities, as also hibalactone, a possible phytoconstituent responsible for the biological effects of this specie.

Novel 3-(1,2,3,6-Tetrahydropyridin-4-yl)-1H-indole-Based Multifunctional Ligands with Antipsychotic-Like, Mood-Modulating, and Procognitive Activity.

The most troublesome aspects of behavioral and psychological symptoms of dementia (BPSD) are nowadays addressed by antidepressant, anxiolytic, and antipsychotic drugs, often administered off-label. Considering their modest effectiveness in dementia patients, the increased risk of adverse events and cognitive decline, there is an unmet need for well-tolerated and effective therapy of BPSD. We designed and synthesized multifunctional ligands characterized in vitro as high-affinity partial agonists of D2R, antagonists of 5-HT6R, and blockers of SERT. Moreover, the molecules activated 5-HT1AR and blocked 5-HT7R while having no relevant affinity for off-target M1R and hERG channel. Compound 16 (N-{2-[4-(5-chloro-1H-indol-3-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl}-3-methylbenzene-1-sulfonamide) exhibited a broad antipsychotic-, antidepressant-, and anxiolytic-like activity, not eliciting motor impairments in mice. Most importantly, 16 showed memory-enhancing properties and it ameliorated memory deficits induced by scopolamine. The molecule outperformed most important comparators in selected tests, indicating its potential in the treatment of both cognitive and noncognitive (behavioral and psychological) symptoms of dementia.

Evidence for the involvement of the GABAergic, but not serotonergic transmission in the anxiolytic-like effect of bisabolol in the mouse elevated plus maze.

Bisabolol (α-(-)-bisabolol) is a sesquiterpene which is a part of the essential oil of a variety of plants, but its common source is German chamomile. Several bioactivities including anti-inflammatory, anti-nociceptive, and anti-tumor effects were attributed to bisabolol. However, the neuropharmacological properties of bisabolol have not yet been reported. The present study evaluated behavioral effects of bisabolol using elevated plus maze (EPM), open field test (OFT), and rotarod test. Moreover, this study also examined whether the 5-HT1A and GABAA-benzodiazepine receptor systems are involved in the anxiolytic-like effects of bisabolol. After acute intraperitoneal treatment with bisabolol at the doses of 0.5, 1, 2, 5, and 10mg/kg, OFT, EPM, and rotarod were utilized for investigating behavioral effects. Flumazenil, a benzodiazepine receptor antagonist, and WAY-100635, a 5-HT1A receptor antagonist, were used to determine the action mechanism in the EPM. Bisabolol especially at the dose of 1mg/kg was effective in increasing the total number of entries and time spent in the open arms of EPM while number of rearing and grooming in OFT was decreased in comparison to the control. In the rotarod, permanence time was decreased in the mice treated with the high doses of bisabolol. Pretreatment with flumazenil, but not WAY-100635, was able to reverse the effect of bisabolol 1mg/kg in the EPM, indicating that the anxiolytic-like activity of bisabolol occurs via the GABAergic but not serotonergic transmission. The present study supports the idea that bisabolol may mediate its anxiolytic-like and sedative mechanisms involving GABAA receptors.

Antioxidant-mediated neuro-protective and GABAergic calming effect of Stephania japonica

Stephania japonica, a tropically-habituated plant is widely distributed in Bangladesh. Traditionally, it has been used in the treatment of inflammation, asthma, fever, sleep disturbance, painful conditions, and rheumatism. However, scientific evidence of its biological activities are very limited. This study evaluated neuroprotctivity along with a possible anxiolytic-like effect of the methanol leaf extract of S. japonica (MSJ). The antioxidant test was performed by using the scavenging capacity of hydroxyl (●OH) and nitric oxide (●OH) radicals; and an inhibition of lipid peroxidation assay. In vitro, egg albumin denaturation (IELD) and anti-acetylcholinesterase (anti-AChE) tests were performed to evaluate the anti-inflammatory and anti-cholinesterase activity, respectively. Additionally, a possible anxiolytic action of the MSJ was investigated in Swiss mice by taking diazepam (DZP) and flumazenil (FLU) as gamma amino butyric acid (GABA) receptor agonist and antagonist, respectively. The MSJ concentration (50-200 µg/mL)/dose (50-200 mg/kg, oral)-dependently exhibited antioxidant, anti-inflammatory, anti-AChE and anxiolytic-like effects. The MSJ also increased the activities of the standards used in antioxidant and anti-AChE (trolox), anti-inflammatory (acetyl salicylic acid), and anxiolytic (DZP: agonist) test. The MSJ exhibited antioxidant and anti-inflammatory activities. It also potentiated the action of DZP, while antagonizing the effect of the FLU, suggesting a possible GABAergic, DZP-agonistic anxiolytic-like action in experimental animals. S. japonica may be one of the good sources of neuroprotective phytochemicals.

HBK-15 protects mice from stress-induced behavioral disturbances and changes in corticosterone, BDNF, and NGF levels

Unlike majority of current antidepressants, HBK-15–a 5-HT1A and 5-HT7 receptor antagonist – showed memory-enhancing properties. In this study, we aimed to further characterize pharmacological profile of HBK-15 and investigate its antidepressant- and anxiolytic-like activity in the mouse model of unpredictable chronic mild stress. We used sucrose consumption test, forced swim test and elevated plus maze test as behavioral endpoints. We also evaluated the influence of HBK-15 on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the hippocampus and prefrontal cortex, as well as body weight, relative adrenal glands weight and plasma corticosterone level in the stressed mice. We utilized LC/MS/MS method to determine HBK-15 concentration in plasma and brain. We evaluated pharmacokinetic profile and distribution to brain of HBK-15 (2.5mg/kg) after intravenous (i.v.) and intraperitoneal (i.p.) administration in CD-1 mice. HBK-15 (2.5mg/kg but not 1.25mg/kg) and fluoxetine (10mg/kg) protected stressed mice from anhedonic-, depressive- and anxiety-like behaviors, decreases in the BDNF and NGF levels in the hippocampus and prefrontal cortex, increases in plasma corticosterone levels and relative adrenal glands weight. The pharmacokinetic analysis demonstrated a rapid absorption of HBK-15 after i.p. administration (tmax=5min), a short half-life (t0.5=74min), large volume of distribution (Vss=3.7L/kg) and bioavailability after i.p. administration equal 25%. HBK-15 administered i.v. and i.p. significantly penetrated brain. Our results suggest that the blockade of serotonergic 5-HT1A and 5-HT7 receptors might be beneficial in the treatment of depressive disorders with cognitive dysfunction.

Single Administration of HBK-15\u2014a Triple 5-HT1A, 5-HT7, and 5-HT3 Receptor Antagonist\u2014Reverses Depressive-Like Behaviors in Mouse Model of Depression Induced by Corticosterone

Studies suggest that the blockade of 5-HT1A, 5-HT7, and 5-HT3 receptor may increase the speed of antidepressant response. 1-[(2,6-Dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15), dual 5-HT1A and 5-HT7 antagonists, showed significant antidepressant- and anxiolytic-like properties in our previous tests in rodents. In this study, we aimed to investigate their antidepressant potential using mouse model of corticosterone-induced depression. We chose sucrose preference test, forced swim test, and elevated plus maze to determine anhedonic-, antidepressant-, and anxiolytic-like activities. We also evaluated the influence of the active compound on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the hippocampus. Moreover, for both compounds, we performed biofunctional (5-HT3 receptor) and pharmacokinetic studies. We found that HBK-14 and HBK-15 were potent 5-HT3 receptor antagonists. HBK-14 (2.5 mg/kg) and HBK-15 (1.25 mg/kg) after intravenous (i.v.) and intraperitoneal (i.p.) administration permeated the blood–brain barrier with brain/plasma ratio lower than 1. The bioavailability of studied compounds after i.p. administration was 15% for HBK-14 and 54% for HBK-15. Chronic administration of HBK-15 (1.25 mg/kg) and fluoxetine (10 mg/kg) protected corticosterone-treated mice from anhedonic-, depressive-, and anxiety-like behaviors, as well as decreases in BDNF and NGF levels in the hippocampus. HBK-14 (2.5 mg/kg) counteracted anxiety-like behaviors in corticosterone-treated mice. Single administration of HBK-15 (1.25 mg/kg) and ketamine (1 mg/kg) reversed depression-like behavior and regulated decreased BDNF level in the hippocampus in corticosterone-treated mice. Our results suggest that simultaneous blockade of serotonergic 5-HT1A, 5-HT7, and 5-HT3 receptors might accelerate antidepressant response.