Potential Antidepressant-like Activity Research Articles

Repeated Sulforaphane Treatment Reverses Depressive-like Behavior and Exerts Antioxidant Effects in the Olfactory Bulbectomy Model in Mice.

Growing evidence suggests that activators of nuclear factor erythroid-derived 2-like 2 (Nrf2), such as sulforaphane, may represent promising novel pharmacological targets for conditions related to oxidative stress, including depressive disorder. Therefore, we conducted a study to explore the behavioral and biochemical effects of repeated (14 days) sulforaphane (SFN) treatment in the olfactory bulbectomy (OB) animal model of depression. An open field test (OFT), splash test (ST), and spontaneous locomotor activity test (LA) were used to assess changes in depressive-like behavior and the potential antidepressant-like activity of SFN. The OB model induced hyperactivity in mice during the OFT and LA as well as a temporary loss of self-care and motivation in the ST. The repeated administration of SFN (10 mg/kg) effectively reversed these behavioral changes in OB mice across all tests. Additionally, a biochemical analysis revealed that SFN (10 mg/kg) increased the total antioxidant capacity in the frontal cortex and serum of the OB model. Furthermore, SFN (10 mg/kg) significantly enhanced superoxide dismutase activity in the serum of OB mice. Overall, the present study is the first to demonstrate the antidepressant-like effects of repeated SFN (10 mg/kg) treatment in the OB model and indicates that these benefits may be linked to improved oxidative status.

1-(Phenylselanyl)-2-(p-tolyl)indolizine: A selenoindolizine with potential antidepressant-like activity in mice mediated by the modulation of dopaminergic and noradrenergic systems

1-(Phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) is a selenoindolizine with an antidepressant-like effect in mice by regulation of the serotonergic system. This study investigated the involvement of dopaminergic and noradrenergic systems in the antidepressant-like action of MeSeI. For this purpose, Swiss male mice were pretreated with different antagonists, after 15 min, the MeSeI was administrated by intragastric (i.g.) via; after 30 min, the mouse behavior was assessed in the forced swimming test (FST). The action of MeSeI on the activity of monoamine oxidase (MAO) was determined. The pretreatment of mice with haloperidol (0.05 mg/kg, intraperitoneally, i.p.; non-selective dopamine receptor antagonist), sulpiride (50 mg/kg, i.p.; D2 receptor antagonist), yohimbine (1 mg/kg, i.p.; α2 receptor antagonist), and propranolol (2 mg/kg, i.p.; non-selective β receptor antagonist), inhibited the anti-immobility action of MeSeI (50 mg/kg, i.g.) in the FST. This blocking effect was not observed when SCH23390 (0.01 mg/kg, i.p.; D1 receptor antagonist), and prazosin (1 mg/kg, i.p.; α1 receptor antagonist) were administered. The coadministration of subeffective doses of bupropion (3 mg/kg. i.g.; dopamine and noradrenaline reuptake inhibitor) and MeSeI (0.5 mg/kg. i.g.) reduced the immobility time in the FST. Furthermore, MeSeI inhibited MAO-A and B activities in vitro and ex vivo tests. These results suggest that MeSeI exerts its antidepressant-like effect via regulation of the D2, α2, and β1 receptors and the inhibition of MAO-A and B activities. Molecular docking investigations corroborated these results. This study provides comprehensive insights into the antidepressant-like mechanism of MeSeI in mice, suggesting its potential as a novel antidepressant candidate.

Sigma-1 receptor activation mediates the sustained antidepressant effect of ketamine in mice via increasing BDNF levels.

Sigma-1 receptor (S1R) is a unique multi-tasking chaperone protein in the endoplasmic reticulum. Since S1R agonists exhibit potent antidepressant-like activity, S1R has become a novel target for antidepression therapy. With a rapid and sustained antidepressant effect, ketamine may also interact with S1R. In this study, we investigated whether the antidepressant action of ketamine was related to S1R activation. Depression state was evaluated in the tail suspension test (TST) and a chronic corticosterone (CORT) procedure was used to induce despair-like behavior in mice. The neuronal activities and structural changes of pyramidal neurons in medial prefrontal cortex (mPFC) were assessed using fiber-optic recording and immunofluorescence staining, respectively. We showed that pharmacological manipulation of S1R modulated ketamine-induced behavioral effect. Furthermore, pretreatment with an S1R antagonist BD1047 (3 mg·kg-1·d-1, i.p., for 3 consecutive days) significantly weakened the structural and functional restoration of pyramidal neuron in mPFC caused by ketamine (10 mg·kg-1, i.p., once). Ketamine indirectly triggered the activation of S1R and subsequently increased the level of BDNF. Pretreatment with an S1R agonist SA4503 (1 mg·kg-1·d-1, i.p., for 3 consecutive days) enhanced the sustained antidepressant effect of ketamine, which was eliminated by knockdown of BDNF in mPFC. These results reveal a critical role of S1R in the sustained antidepressant effect of ketamine, and suggest that a combination of ketamine and S1R agonists may be more beneficial for depression patients.

Potential Antidepressant-Like Activity of Rhus coriaria L. (Sumac) Ethanolic Extract: The Mechanism of Action via the Monoaminergic System in a Mouse Model

Background: Studies have reported certain side effects that occur with the use of conventional antidepressants limit their clinical use. Plant derivatives such as Rhus coriaria L. extract can be used as alternatives for depression. Objectives: This study was designed to investigate the antidepressant-like effects of R. coriaria in a mouse model and the role of the monoaminergic system in its mechanism of action. Methods: A total of 174 male NMRI mice were used. Thirty minutes after treating animals with common antidepressants and R. coriaria extract (25 - 200 mg/kg), the tail suspension test (TST) was performed. One hour after treating mice with serotonergic, adrenergic, and dopaminergic antagonists, 100 mg/kg of the extract was administered, and TST was performed after 30 minutes. Potential synergistic interactions between the extract and the sub-doses of fluoxetine (Flx) and imipramine (Imp) were also investigated. Injections were all administered intraperitoneally. Results: Rhus coriaria extract (50 - 200 mg/kg) induced antidepressant-like effects (P < 0.001) without altering animal locomotion in the open field test (OFT; P > 0.05). The tail suspension test showed that the antidepressant-like activity of the extract was blocked by pretreating with the above-mentioned antagonists (P < 0.05 and P < 0.01, respectively). The sub-dose of the extract also increased the efficiency of the sub-doses of common antidepressants (P < 0.001). Conclusions: The extract showed antidepressant-like activity via the monoaminergic system and increased the efficiency of common antidepressants. We suggest adding dried R. coriaria extract powder to the formulation of common antidepressant agents following thorough clinical studies on the substance.

Anti-depressant Potentials of Some Bioactive Components of Basella alba Leaves in Chronic Unpredictable Stress Rat Model

Bioactive components of Basella alba leaves are responsible for their antidepressant-like activity. However, the component with the greatest anti-depressant activity is unknown. This study investigated the antidepressant-like activities of the bioactive components (phenols, flavonoids, and glycosides) in Basella alba leaves. Forty-two male Wistar rats weighing 50–200 g were randomly divided into six groups (n=7). All the groups, except for the control, were subjected to chronic unpredictable stress (CUS) for five weeks. The rats in the CUS groups were treated with normal saline (1 mL/kg), escitalopram (5 mg/kg), and each of the phenol-, flavonoid-, and glycoside-rich Basella alba extracts (200 mg/kg) orally for twenty-one days. The tail suspension, sucrose preference, light-dark box, and hole-board tests were carried out before and after the induction of depression. In the CUS groups, reduced mobility time on tail suspension, increased percentage sucrose consumption, frequency of head dips on the hole board, and line-cross frequency in the light-dark box were observed. The latency on the hole board was reduced with Basella alba components, while there was a significant (p<0.05) decrease in serum brain-derived neurotrophic factor and an increase in serum IL-6 in the CUS animals not treated with extracts. The phenol-rich Basella alba extract showed the most potent antidepressant-like activity, followed by the flavonoid-rich extract. The bioactive components of Basella alba, particularly phenols, were effective in ameliorating the depressive features of CUS and should be further studied for use as an adjunct or stand-alone antidepressant.

Potential Anti-Amnesic Activity of a Novel Multimodal Derivative of Salicylamide, JJGW08, in Mice.

Memory impairments constitute a significant problem worldwide, and the COVID-19 pandemic dramatically increased the prevalence of cognitive deficits. Patients with cognitive deficits, specifically memory disturbances, have underlying comorbid conditions such as schizophrenia, anxiety, or depression. Moreover, the available treatment options have unsatisfactory effectiveness. Therefore, there is a need to search for novel procognitive and anti-amnesic drugs with additional pharmacological activity. One of the important therapeutic targets involved in the modulation of learning and memory processes are serotonin receptors, including 5-HT1A, 5-HT6, and 5-HT7, which also play a role in the pathophysiology of depression. Therefore, this study aimed to assess the anti-amnesic and antidepressant-like potential of JJGW08, a novel arylpiperazine alkyl derivative of salicylamide with strong antagonistic properties at 5-HT1A and D2 receptors and weak at 5-HT2A and 5-HT7 receptors in rodents. First, we investigated the compound's affinity for 5-HT6 receptors using the radioligand assays. Next, we assessed the influence of the compound on long-term emotional and recognition memory. Further, we evaluated whether the compound could protect against MK-801-induced cognitive impairments. Finally, we determined the potential antidepressant-like activity of the tested compound. We found that JJGW08 possessed no affinity for 5-HT6 receptors. Furthermore, JJGW08 protected mice against MK-801-induced recognition and emotional memory deficits but showed no antidepressant-like effects in rodents. Therefore, our preliminary study may suggest that blocking serotonin receptors, especially 5-HT1A and 5-HT7, might be beneficial in treating cognitive impairments, but it requires further investigation.

Neuropharmacological Activity of the New Piperazine Derivative 2-(4-((1- Phenyl-1H-Pyrazol-4-yl)Methyl)Piperazin-1-yl)Ethyl Acetate is Modulated by Serotonergic and GABAergic Pathways.

Pharmacological treatments for mental disorders, such as anxiety and depression, present several limitations and adverse effects. Therefore, new pharmacotherapy with anxiolytic and antidepressant potential is necessary, and the study of compounds capable of interacting with more than one pharmacological target may provide new therapeutic options. In this study, we proposed the design, synthesis of a new compound, 2-(4-((1- phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethyl acetate (LQFM192), pharmacological evaluation of its anxiolytic-like and antidepressant-like activities, as well as the possible mechanisms of action involved. Administration of LQFM192 was carried out prior to the exposure of male Swiss mice to behavioral tests, such as the elevated plus-maze and forced swimming test. The involvement of the serotonergic system was studied by pretreatment with WAY-100635 or p-chlorophenylalanine (PCPA) and the involvement of the benzodiazepine site of the GABAA receptor by pretreatment with flumazenil. The treatment with LQFM192 at doses of 54 and 162 μmol/kg demonstrated anxiolyticlike activity that was blocked by WAY-100635, PCPA, and flumazenil pretreatments. The potential antidepressant-like activity was visualized at the same doses and blocked by WAY-100635 and PCPA. In summary, the anxiolytic-like activity of LQFM192 is mediated by the serotonergic system and the benzodiazepine site of the GABAA receptor, and the antidepressant-like activity through the serotonergic system.

Antidepressant-like effects of dezocine in mice: involvement of 5-HT1A and κ opioid receptors.

Dezocine is an opioid with low efficacy at μ-opioid and κ-opioid receptors. It also inhibits the reuptake of norepinephrine and serotonin. Dezocine is an effective analgesic against various clinical painful conditions and is widely used in many Asian countries. Given the unique pharmacology of dezocine, the drug may also have antidepressant-like properties. However, no published preclinical study has explored this possibility. This study examined the potential antidepressant-like activity of dezocine in mice. Male ICR mice were used in the forced swimming test, the tail suspension test, the warm water tail withdrawal test and locomotor activity test to test the effects of dezocine (0.3-3.0 mg/kg). The 5-HT1A receptor antagonist WAY-100635 (1 mg/kg), the μ-opioid receptor antagonist β-funaltrexamine (2 mg/kg) and the κ-opioid receptor agonist U50488 (1 mg/kg) were also studied in combination with dezocine. Dezocine produced a dose-dependent decrease in the immobility time in the forced swimming test and tail suspension test at doses that did not alter the motoric activity as determined in the locomotion test. WAY-100635 and U50488 but not β-funaltrexamine pretreatment significantly blocked the effects of dezocine. Dezocine dose-dependently increased the latency in the tail withdrawal test which was blocked by WAY-100635 and β-funaltrexamine. Combined, these results suggest that dezocine may have antidepressant-like effects. Considering the well-documented analgesic property of dezocine, it may be useful to treat pain and depression comorbidity.

Synthesis, In Silico Studies, and Biological Evaluation of 1,3,4-Oxadiazino Indole Derivatives.

New series of substituted 2-[4-pyridyl](1,3,4)oxadiazino(5,6-b)indole derivatives were synthesized and evaluated for in silico studies. Based on in silico studies, the selected compounds were synthesized and evaluated for their antidepressant activity by forced swim test. Among these compounds, compound IVD was found to be most potent antidepressant-like activity and significantly reduced the duration of immobility at 100mg/kg dose level when compared to the vehicle control which is similar to the reference drug imipramine (10mg/kg).

Influence of the endocannabinoid system on the antidepressant activity of bupropion and moclobemide in the behavioural tests in mice

BackgroundThough there are several classes of antidepressant drugs available on the pharmaceutical market, depression that affects globally over 320 million people is still undertreated. Scientists have made attempts to develop novel therapeutical strategies to maximize effectiveness of therapy and minimize undesired reactions. One of the ideas is use of either dual-action agents or combined administration of two substances that affect diverse neurotransmissions. Thus, we investigated whether the selected CB receptor ligands (oleamide, AM251, JWH133, and AM630) can have an impact on the activity of bupropion and moclobemide. Bupropion belongs to the dual acting drugs, whereas moclobemide is an inhibitor of monoamine oxidase.MethodsThe mice forced swim test and the tail suspension test were applied in order to determine the potential antidepressant-like activity, whereas the HPLC method was used in order to assess the brain concentrations of the tested antidepressants.ResultsAn intraperitoneal injection of sub-effective doses of oleamide (5 mg/kg), AM251 (0.25 mg/kg), and AM630 (0.25 mg/kg) increased activity of bupropion (10 mg/kg) in both behavioural tests. Effects of moclobemide (1.5 mg/kg) were potentiated only by AM251. These results were not influenced by the hypo- or hyperlocomotion of animals.ConclusionThe outcomes of the present study revealed that particularly activation or inhibition of the CB1 receptor function may augment the antidepressant activity of bupropion, whereas only inhibition of the CB1 receptor function manages to increase activity of moclobemide. Most probably, an interplay between CB receptor ligands and bupropion or moclobemide takes place at the cellular level.

Dipeptide tyrosyl-leucine exhibits antidepressant-like activity in mice

Depression is a worldwide health problem. In the present study, we found that a dipeptide, tyrosyl leucine (Tyr-Leu, YL), administered orally, intracerebroventricularly, or intraperitoneally exhibited a potent antidepressant-like activity in the forced swim and tail suspension tests in naïve mice. YL increased the amount of cells expressing c-Fos, a marker for neuronal activity, in the dentate gyrus of the hippocampus. YL increased bromo-2′-deoxyuridine-positive cells and doublecortin expression in the dentate gyrus of the hippocampus, suggesting that YL enhanced the proliferation of hippocampal progenitor cells in vivo and in vitro. YL did not affect hippocampal mRNA and protein expression of BDNF, which is a regulatory factor of both neurogenesis and depression-like behavior. Intriguingly, YL suppressed activation of the hypothalamo-pituitary-adrenal axis by forced swim stress. Moreover, other aromatic amino acid-leucines, Phe-Leu and Trp-Leu, also exhibited antidepressant-like activities, suggesting that the structure of aromatic amino acid-leucine may be important for antidepressant activity. In addition, bovine milk casein-derived peptide, Tyr-Leu-Gly (YLG), an anxiolytic peptide, exhibited an antidepressant-like activity. Our findings demonstrate that YL exhibits an antidepressant-like effect, moderates the stress response, and induces hippocampal neuronal proliferation through a signal pathway independent of BDNF.

Beneficial effects of nano-curcumin supplement on depression and anxiety in diabetic patients with peripheral neuropathy: A randomized, double-blind, placebo-controlled clinical trial.

Depression in patients with diabetes is associated with poor glycemic control and linked to an increased risk for diabetes complications such as neuropathy. Curcumin has shown potential antidepressant-like activities in some studies. The present study is the first randomized controlled trial to test the efficacy of nano-curcumin supplementation on depression, anxiety, and stress in patients with diabetic polyneuropathy. Eighty patients with diabetes were enrolled in this parallel, double-blind, randomized, placebo-controlled clinical trial. The participants were allocated randomly to the intervention (n = 40) and control (n = 40) groups. They received 80 mg of nano-curcumin or placebo capsules daily for 8 weeks. At baseline and end of study, anthropometric measurements, dietary intake, physical activity, glycemic indices, and severity of neuropathy were assessed. The depression, anxiety, and stress level were measured by Depression, Anxiety, Stress Scale (DASS-21-items) questionnaire before and after the intervention. After intervention, there was a significant reduction in the mean score of depression in the nano-curcumin group (from 16.7 [3.1] to 15.3 [2.6]) compared with placebo group (17.5 [3.2] to 17.3 [3.1]; p = .02). In addition, a significant fall was found in the mean score of anxiety in the nano-curcumin group (from 22.4 [4.03] to 20.6 [3.4]) compared with the placebo group (21.9 [3.5] to 21.2 [3.5]; p = .009). Changes in stress score were not statistically significant between the two groups. These findings suggested that nano-curcumin supplementation for 8 weeks was effective in reducing depression and anxiety scores in patients with diabetic polyneuropathy.

Pharmacological evidence for the involvement of the opioid system in the antidepressant-like effect of simvastatin in mice: Without tolerance and withdrawal syndrome

Statins, 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors, have been shown to be effective in reducing depression in animal models. The present study aimed to investigate the potential antidepressant-like activity of simvastatin and the possible involvement of opioid systems in the mouse forced swimming test (FST). After assessment of locomotor behavior in the open-field test (OFT), FST was applied for evaluation of depressive behavior in mice. Simvastatin (20, 30, and 40 mg/kg, i.p.) or morphine (0.01, 0.1, 1 and 10 mg/kg, i.p.) were administrated 30 min before the OFT or FST. Results showed that simvastatin produced antidepressant effect in a dose-dependent manner. The effect of simvastatin (30 mg/kg) was prevented by the pre-treatment of mice with naloxone (1 mg/kg, i.p., a nonselective opioid receptor antagonist). In addition, a sub-effective dose of simvastatin (20 mg/kg) produced a synergistic antidepressant-like effect in the FST with a sub-effective dose of morphine (0.1 mg/kg) that it was reversed by naloxone. Moreover, in contrast to morphine, treatment with simvastatin for six days induced neither tolerance to the antidepressant-like effect nor withdrawal signs. In conclusion, these findings demonstrated that simvastatin elicited antidepressant-like action possibly through the stimulation of opioidergic pathways, without inducing tolerance and withdrawal signs.

Design, synthesis and evaluation of activity and pharmacokinetic profile of new derivatives of xanthone and piperazine in the central nervous system.

Searching for CNS active cyclic amines derivatives containing heterocyclic xanthone core we designed and synthesized a set of fourteen novel 2- or 4-methylxanthone substituted by alkyl- or aryl-piperazine moieties. The compounds were evaluated in vivo for their potential antidepressant-like activity (in the forced swim test) and anxiolytic-like activity (four-plate test) and their inhibitory effect against rat 5-HT2 receptor was checked. The pharmacokinetic analysis of active compounds done by a non-compartmental approach have shown a rapid absorption of all studied molecules from intraperitoneal cavity and good penetration the blood-brain barrier after i.p. administration with brain to plasma ratios varied from 2.8 to 31.6. Genotoxicity and biotransformation of active compounds were studied. Compound 19 interactions with major classes of GPCRs, uptake systems and ion channels were tested and results indicated that it binds to 5-HT2A, 5-HT2B receptors and sodium channels.

Simvastatin exerts antidepressant-like activity in mouse forced swimming test: Role of NO-cGMP-KATP channels pathway and PPAR-gamma receptors

Simvastatin, one of the lipophilic statins, has been shown to be effective in reducing depression in rodents. The present study aimed to investigate the potential antidepressant-like activity of simvastatin and the possible involvement of NO-cGMP-KATP channels pathway and PPARγ using forced swimming test (FST) in mice. In addition, the interaction between simvastatin and fluoxetine as a reference drug was examined. After assessment of locomotor behavior in the open-field test (OFT), FST was applied for evaluation of depressive behavior in mice. Simvastatin at doses (20, 30, and 40 mg/kg, i.p.) was administrated 30 min before the OFT or FST. To evaluate the involvement of NO-cGMP-KATP channels pathway, mice were pre-treated intraperitoneally with l-arginine (a nitric oxide precursor, 750 mg/kg), L-NAME (a NOS inhibitor, 10 mg/kg), methylene blue (guanylyl cyclase inhibitor, 20 mg/kg), sildenafil (a PDE-5 inhibitor, 5 mg/kg), glibenclamide (ATP-sensitive K+ channel blocker, 1 mg/kg), and diazoxide (K+ channels opener, 10 mg/kg). Moreover, to clarify the probable involvement of PPARγ receptors, pioglitazone, a PPARγ agonist (5 mg/kg, i.p.), and GW9662, a PPARγ antagonist (2 mg/kg, i.p.), were pre-treated with simvastatin. Immobility time was significantly decreased after simvastatin injection. Administration of L-NAME, methylene blue, glibenclamide and pioglitazone in combination with the sub-effective dose of simvastatin (20 mg/kg, i.p.) reduced the immobility time in the FST compared to drugs alone, while co-administration of effective doses of simvastatin (30 mg/kg, i.p.) with l-arginine, sildenafil, diazoxide, and GW9662 prevented the antidepressant-like effect of simvastatin. In addition, simvastatin (20 mg/kg) potentiated the antidepressant-like effect of fluoxetine through the NO pathway. None of the drugs produced any significant alterations in locomotor activity using OFT. These results demonstrated that NO-cGMP-KATP channels pathway and PPARγ receptors may be involved in the antidepressant-like effect of simvastatin.

Antidepressant-like effect of salidroside and curcumin on the immunoreactivity of rats subjected to a chronic mild stress model

Deregulated cytokines' production is found in depressed patients. Salidroside and curcumin both have been described with potential antidepressant-like activities. The present study investigated the effect of pure salidroside, curcumin and their combination on the immunoreactivity of animals, subjected to a chronic mild stress (CMS) model, followed by lipopolysaccharide (LPS)-induced inflammation. Wistar male rats were separated in the following six groups: control, CMS model, fluoxetine (2.5 mg/kg, oral), salidroside (5 mg/kg, oral), curcumin (20 mg/kg, oral) and salidroside + curcumin (5 mg/kg + 20 mg/kg, oral). Changes in glucose preference, spatial learning and exploratory behavior were recorded. The IL-6 levels in the rats' sera and of the TNF-α levels in the rats' sera and the brain tissue homogenate were evaluated. The groups exposed to stress and treated with fluoxetine, salidroside, curcumin or salidroside + curcumin showed increase in the glucose preference and locomotor activity, as well as, decrease in the escape latency and the cytokines' levels compared to the CMS model group. The chronic stress induced behavioral alternations and increased cytokines’ levels in rats which were reversed by administration of salidroside and curcumin, suggesting antidepressant-like effects comparable to that of fluoxetine and potential synergistic interaction regarding the anti-inflammatory and anti-stress effects.

HBK-14 and HBK-15, triple 5-HT1A, 5-HT7 and 5-HT3 antagonists with potent antidepressant- and anxiolytic-like properties, increase seizure threshold in various seizure tests in mice

Most antidepressants lower seizure threshold, which might be due to the modulation of serotonergic neurotransmission. Here, we investigated the effects of two 5-HT1A, 5-HT7 and 5-HT3 antagonists, i.e., 1-(2-(2-(2,6-dimethylphenoxy)ethoxy)ethyl)-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-{2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15), with antidepressant- and anxiolytic-like properties, on seizure thresholds in three acute seizure tests, i.e., the intravenous pentylenetetrazole, maximal electroshock seizure threshold (MEST), and 6-Hz corneal stimulation test in mice. We also evaluated their affinity for voltage-gated sodium channels. Our results indicate that HBK-14 increased seizure thresholds in three seizure tests in mice, while HBK-15 was active in the MEST and 6-Hz tests. None of the compounds affected neuromuscular strength or motor coordination at active doses. We showed that both compounds had high affinity for voltage-dependent sodium channels, which combined with the influence on 5-HT1A, 5-HT7 and 5-HT3 receptors, might underlie their anticonvulsant effects. Since most antidepressants lower the seizure threshold, the fact that both compounds with potent antidepressant-like activity, increased or had no influence on seizure threshold is worth investigating.

Potential antidepressant-like activity of silymarin in the acute restraint stress in mice: Modulation of corticosterone and oxidative stress response in cerebral cortex and hippocampus.

Silymarin is a polyphenolic flavanoid of Silybum marianum, elicited neuroprotection and antidepressant like activity in stressed model. It was found to increase 5-hydroxytryptamine (5-HT) levels in the cortex and dopamine (DA) and norepinephrine (NE) in the cerebellum in normal mice. The aim of the present study was to investigate the potential antidepressant-like activity of silymarin in the acute restraint stress (ARS) in mice. The ARS was induced by immobilizing the mice for a period of 7h using rodent restraint device preventing them for any physical movement. One hour prior to ARS, silymarin was administered at doses of 100mg/kg and 200mg/kg per oral to non stressed and ARS mice. Various behavioral parameters like immobility time in force swim test, locomotor activity in open field test, and biochemical alterations, serum corticosterone, 5-HT, DA, NE level, malondialdehyde (MDA), and antioxidant enzymes (GSH, CAT and SOD) in hippocampus and cerebral cortex in non stressed and ARS subjected mice were investigated. Experimental findings reveals mice subjected to ARS exhibited significant increase immobility time, serum corticosterone, MDA formation and impaired SOD and CAT activities in hippocampus and cerebral cortex as compared to non stressed mice. Silymarin treatment (100mg/kg and 200mg/kg) significantly attenuated immobility time, corticosterone and restored the antioxidant enzymes after ARS. The present experimental findings indicate that silymarin exhibits antidepressant like activity probably either through alleviating oxidative stress by modulation of corticosterone response, and antioxidant defense system in hippocampus and cerebral cortex in ARS mice.

Design, Synthesis, and Potential Antidepressant-like Activity of 7-prenyloxy-2,3-dihydroflavanone Derivatives.

A series of 7-prenyloxy-2, 3-dihydroflavanone derivatives were synthesized and screened for their antidepressant-like activity. Among them, it was observed that compounds 5j and 5k were found to be the most antidepressant-like activity. In addition, it was found that compounds 5j and 5k significantly increased the concentrations of the main neurotransmitters 5-HT and NE in the hippocampus, hypothalamus, and cortex. Compounds 5j and 5k also significantly increased the contents of 5-HIAA in the hippocampus and cortex, shut down 5-HT metabolism compared with mice treated with stress vehicle. These results suggested that compounds 5j and 5k displayed potent antidepressant-like properties that were mediated via neurochemical systems.

Antidepressant- and Anxiolytic-Like Effects of New Dual 5-HT₁A and 5-HT₇ Antagonists in Animal Models.

The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14—FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15—FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds.