Antidepressant Potential Research Articles

Binding Affinity and Mechanisms of Potential Antidepressants Targeting Human NMDA Receptors.

Depression, a mental disorder that plagues the world, is a burden on many families. There is a great need for new, fast-acting antidepressants to be developed. N-methyl-D-aspartic acid (NMDA) is an ionotropic glutamate receptor that plays an important role in learning and memory processes and its TMD region is considered as a potential target to treat depression. However, due to the unclear binding sites and pathways, the mechanism of drug binding lacks basic explanation, which brings great complexity to the development of new drugs. In this study, we investigated the binding affinity and mechanisms of an FDA-approved antidepressant (S-ketamine) and seven potential antidepressants (R-ketamine, memantine, lanicemine, dextromethorphan, Ro 25-6981, ifenprodil, and traxoprodil) targeting the NMDA receptor by ligand-protein docking and molecular dynamics simulations. The results indicated that Ro 25-6981 has the strongest binding affinity to the TMD region of the NMDA receptor among the eight selected drugs, suggesting its potential effective inhibitory effect. We also calculated the critical binding-site residues at the active site and found that residues Leu124 and Met63 contributed the most to the binding energy by decomposing the free energy contributions on a per-residue basis. We further compared S-ketamine and its chiral molecule, R-ketamine, and found that R-ketamine had a stronger binding capacity to the NMDA receptor. This study provides a computational reference for the treatment of depression targeting NMDA receptors, and the proposed results will provide potential strategies for further antidepressant development and is a useful resource for the future discovery of fast-acting antidepressant candidates.

A comprehensive review of phytochemical components as potential antidepressants

Depression is a heterogeneous mood disorder that has been classified and treated in a variety of ways. Despite the fact that a variety of synthetic medications are utilized as conventional treatment for clinically depressed patients, these drugs have side effects that can jeopardize the therapeutic outcome. In recent decades, there has been a rise in research and interest in the psychopharmacology of natural treatments. Thus, it’s worthwhile researching for antidepressants derived from plants that have a demonstrated effect and a favorable benefit-to-risk ratio. By virtue of their medicinal constituents, a variety of medicinal plants and medicines produced from these plants have exhibited antidepressant properties. As a result, major pharmaceutical companies are currently researching plant materials extensively for their possible medical benefit. Depression is caused by low levels of monoamines such as noradrenaline, dopamine, and serotonin in the brain. Therefore, treatments that restore lowered levels of these monoamines in the brain by blocking monoamine oxidase or decreasing reuptake of these neurotransmitters could be beneficial in the treatment of depression. The current review focuses on medicinal plants and plant-based formulations that have been shown to have antidepressant effect in both animal and human studies.

Exploring unbinding mechanism of drugs from SERT via molecular dynamics simulation and its implication in antidepressants

The human serotonin transporter (SERT) terminates neurotransmission by removing serotonin from the synaptic cleft, which is an essential process that plays an important role in depression. In addition to natural substrate serotonin, SERT is also the target of the abused drug cocaine and, clinically used antidepressants, escitalopram, and paroxetine. To date, few studies have attempted to investigate the unbinding mechanism underlying the orthosteric and allosteric modulation of SERT. In this article, the conserved property of the orthosteric and allosteric sites (S1 and S2) of SERT was revealed by combining the high resolutions of x-ray crystal structures and molecular dynamics (MD) simulations. The residues Tyr95 and Ser438 located within the S1 site, and Arg104 located within the S2 site in SERT illustrate conserved interactions (hydrogen bonds and hydrophobic interactions), as responses to selective serotonin reuptake inhibitors. Van der Waals interactions were keys to designing effective drugs inhibiting SERT and further, electrostatic interactions highlighted escitalopram as a potent antidepressant. We found that cocaine, escitalopram, and paroxetine, whether the S1 site or the S2 site, were more competitive. According to this potential of mean force (PMF) simulations, the new insights reveal the principles of competitive inhibitors that lengths of trails from central SERT to an opening were ∼18 Å for serotonin and ∼22 Å for the above-mentioned three drugs. Furthermore, the distance between the natural substrate serotonin and cocaine (or escitalopram) at the allosteric site was ∼3 Å. Thus, it can be inferred that the potent antidepressants tended to bind at deeper positions of the S1 or the S2 site of SERT in comparison to the substrate. Continuing exploring the processes of unbinding four ligands against the two target pockets of SERT, this study observed a broad pathway in which serotonin, cocaine, escitalopram (at the S1 site), and paroxetine all were pulled out to an opening between MT1b and MT6a, which may be helpful to understand the dissociation mechanism of antidepressants.

Evaluation of the anti-depressant potential of metformin in conditioned defeat model in golden Syrian hamsters

Background: Depression is a prevalent mood condition that has an impact on daily functioning. Globally, depression affects 264 million people. The current pharmacotherapy of depression has a lot of shortcomings. Therefore, there is a need to explore newer therapy that alleviate the symptoms of depression. Metformin was found to possess antioxidant potential and hypothesized to decrease the levels of branched-chain amino-acids essential for tryptophan uptake (precursor for serotonin synthesis). The study was designed to validate the efficacy of metformin as an anti-depressant in conditioned defeat model in male golden Syrian hamsters using open field test (OFT), forced swim test (FST) and Serum serotonin levels. Methods: After obtaining IAEC approval, the study was carried out using eight golden Syrian hamsters that were randomly assigned to four groups. The disease control group received 1mL normal saline, positive control was given fluoxetine 12 mg/kg, two groups of metformin 240 mg/kg given pre-insult and post-insult. The variables assessed on every third day included OFT and FST. Following the behavioral tests, serotonin-ELISA was done. To analyse the outcomes, appropriate statistical tests were applied. Results: On standardization, the model was established to a 16-day model. Further, results highlighted a significant difference in OFT, FST and serotonin levels with the metformin group and fluoxetine compared to disease control (p<0.001). However, no significant difference was observed between the fluoxetine and metformin groups (p>0.05), signifying the comparable results. Conclusions: Metformin (240 mg/kg) alleviated the depressive symptoms by modulating both behavioral and serotonin levels.

Effect of Bromelain on Chronic Unpredictable Stress-induced Behavioral, Biochemical, and Monoamine Changes in Wistar Albino Rat Model of Depression.

Bromelain is a complex mixture of protease enzyme extract from the fruit or stem of the pineapple plant and it has a history of folk medicine use. It is known to have a wide range of biological actions and it is most commonly used as an anti-inflammatory agent, though scientists have also discovered its potential as an anticancer and antimicrobial agent, it has been reported to have positive effects on the respiratory, digestive, circulatory systems and potentially on the immune system. This study was designed to investigate the antidepressant potential of Bromelain in the chronic unpredictable stress (CUS) model of depression. We studied the antioxidant activity, and neuroprotective effect of Bromelain by analyzing the fear and anxiety behavior, antioxidants, and neurotransmitter levels, and also by analyzing the histopathological changes. Adult male Wistar albino rats were divided into 5 groups, Control; Bromelain; CUS; CUS + Bromelain, CUS + fluoxetine. Animals of the CUS group, CUS + Bromelain group, and CUS + Fluoxetine group were exposed to CUS for 30 days. Animals of the Bromelain group and CUS + Bromelain group were treated orally with 40mg/kg Bromelain throughout the period of CUS whereas, the positive control group was treated with fluoxetine. Results showed a significant decrease in oxidative stress marker (lipid peroxidation), and the stress hormone cortisol, in Bromelain-treated CUS-induced depression. Bromelain treatment in CUS has also resulted in a significant increase in neurotransmitter levels, which indicates the efficacy of Bromelain to counteract the monamine neurotransmitter changes in depression by increasing their synthesis and reducing their metabolism. In addition, the antioxidant activity of Bromelain prevented oxidative stress in depressed rats. Also, hematoxylin and eosin staining of hippocampus sections has revealed that Bromelain treatment has protected the degeneration of nerve cells by chronic unpredictable stress exposure. This data provides evidence for the antidepressant-like action of Bromelain by preventing neurobehavioral, biochemical, and monoamine alterations.

(2-Cyclohexyl-1-methylpropyl) cyclohexane isolated from garlic extract exhibits antidepressant-like activity: extraction, docking, drug-like properties, molecular dynamics simulations and MM/GBSA studies

Depressive disorders are among most common psychiatric diseases and second most common form of psychiatric illness globally. Commonly available chemical drugs used for treatment of nervous system disorders exert undesirable effects. Therefore, there is a growing need towards exploring novel antidepressants of herbal origin. Earlier, the antidepressant effect of methanolic extract of garlic has been shown. In this study, the ethanolic extract of garlic was prepared and chemically analysed using Gas Chromatography – Mass Spectrometry (GC-MS) screening. A total of 35 compounds were found to be present, which might act as antidepressant. Using computational analyses, these compounds were screened as potential inhibitors (selective serotonin reuptake inhibitor (SSRI)) against serotonin transporter (SERT)/leucine receptor (LEUT). In silico docking studies and other physicochemical, bioactivity and ADMET studies resulted in the selection of compound 1 ((2-Cyclohexyl-1-methylpropyl) cyclohexane) as potential SSRI (binding energy −8.1 kcal/mol) compared to known reference SSRI fluoxetine (binding energy −8.0 kcal/mol). Analysis of conformational stability, residue flexibility, compactness, binding interactions, solvent accessible surface area (SASA), dynamic correlation, and binding free energy predicted from molecular mechanics (MD) with generalised Born and surface area solvation (MM/GBSA) studies revealed formation of a more stable SSRI like complex with compound 1 having strong inhibitory interaction compared to known SSRI fluoxetine/reference complex. Thus, compound 1 may act as an active SSRI leading to discovery of potential antidepressant drug. Communicated by Ramaswamy H. Sarma

Lateral septum adenosine A2A receptors control stress-induced depressive-like behaviors via signaling to the hypothalamus and habenula

Major depressive disorder ranks as a major burden of disease worldwide, yet the current antidepressant medications are limited by frequent non-responsiveness and significant side effects. The lateral septum (LS) is thought to control of depression, however, the cellular and circuit substrates are largely unknown. Here, we identified a subpopulation of LS GABAergic adenosine A2A receptors (A2AR)-positive neurons mediating depressive symptoms via direct projects to the lateral habenula (LHb) and the dorsomedial hypothalamus (DMH). Activation of A2AR in the LS augmented the spiking frequency of A2AR-positive neurons leading to a decreased activation of surrounding neurons and the bi-directional manipulation of LS-A2AR activity demonstrated that LS-A2ARs are necessary and sufficient to trigger depressive phenotypes. Thus, the optogenetic modulation (stimulation or inhibition) of LS-A2AR-positive neuronal activity or LS-A2AR-positive neurons projection terminals to the LHb or DMH, phenocopied depressive behaviors. Moreover, A2AR are upregulated in the LS in two male mouse models of repeated stress-induced depression. This identification that aberrantly increased A2AR signaling in the LS is a critical upstream regulator of repeated stress-induced depressive-like behaviors provides a neurophysiological and circuit-based justification of the antidepressant potential of A2AR antagonists, prompting their clinical translation.

Molecular Docking, MM-GBSA, and Molecular Dynamics Approach: 5-MeO-DMT Analogues as Potential Antidepressants

Since depression is a common mental illness affecting an estimated 5% of people worldwide, investigators are encouraged to develop effective antidepressants. According to the monoamine-deficiency hypothesis, the underlying pathophysiology of depression is a deficiency of some neurotransmitters (serotonin, norepinephrine, or dopamine) in the central nervous system. The neurotransmitter serotonin has drawn the most attention concerning depression. As per research, 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) elevates inter-synaptic serotonin levels when administered as a single inhalation of vapor from dried toad secretion and leads to higher life satisfaction, convergent thinking, higher ratings of mindfulness, lower ratings of depression, and anxiety. Furthermore, although 5-MeO-DMT lowers stress biomarkers such as cortisol, it is a psychedelic with hallucinogenic effects. In the present study, analogues of 5-MeO-DMT are designed with the hope that they might have better therapeutic activity and lower psychedelic side effects. The current study aimed to look at 5-MeO-DMT analogues as possible antidepressants. We used 70,000 5-MeO-DMT analogues that were sketched using Marvin to conduct a High Throughput Virtual Screening method in hopes of finding potential 5-MeO-DMT analogues against the 5-Hydroxytryptamine 1A receptor (5-HT1AR; 7E2Y.pdb) as an agonist. The prediction of the analogue-protein interaction and the evaluation of the binding affinity is accomplished by employing molecular docking. The Glide XP docking data indicated that a total of 21 compounds had Glide gscores ranging from -11.41 to -6.53 kcal/mol. When compared to the standard 5-MeO-DMT with the binding affinity of -7.75 kcal/mol, 14 compounds showed better binding affinity. Furthermore, Molecular Mechanics -Generalised Born and Surface Area solvation (MM-GBSA) indicated a binding free energy range of -63.55 to -35.37 kcal/mol, and 18 compounds showed better binding free energy than standard 5-MeO-DMT (-41.42 kcal/mol). Through ligand binding interactions with Asp116, Phe361, Phe362, Ser190, Ser199, Val117, Trp358, Ala365, Pro369, Ile189, Tyr195, Ala203, Ile167, Tyr390, Cys120, Trp358, Val364, Ala365, and Leu368, these complexes were stabilized, according to the molecular dynamic simulation of 20453/7E2Y in 100ns.

The Melanocortin System: A Promising Target for the Development of New Antidepressant Drugs.

Major depression is one of the most prevalent mental disorders, causing significant human suffering and socioeconomic loss. Since conventional antidepressants are not sufficiently effective, there is an urgent need to develop new antidepressant medications. Despite marked advances in the neurobiology of depression, the etiology and pathophysiology of this disease remain poorly understood. Classical and newer hypotheses of depression suggest that an imbalance of brain monoamines, dysregulation of the hypothalamic-pituitary-adrenal axis (HPAA) and immune system, or impaired hippocampal neurogenesis and neurotrophic factors pathways are cause of depression. It is assumed that conventional antidepressants improve these closely related disturbances. The purpose of this review was to discuss the possibility of affecting these disturbances by targeting the melanocortin system, which includes adrenocorticotropic hormone-activated receptors and their peptide ligands (melanocortins). The melanocortin system is involved in the regulation of various processes in the brain and periphery. Melanocortins, including peripherally administered non-corticotropic agonists, regulate HPAA activity, exhibit anti-inflammatory effects, stimulate the levels of neurotrophic factors, and enhance hippocampal neurogenesis and neurotransmission. Therefore, endogenous melanocortins and their analogs are able to complexly affect the functioning of those body's systems that are closely related to depression and the effects of antidepressants, thereby demonstrating a promising antidepressant potential.

Anxiolytic and Antidepressant Potential of Methanolic Extract of Neurada procumbens Linn. in Mice.

Neurada procumbens Linn. possesses a wide range of phytochemical and bioactive entities such as flavonoids and polyphenols that decrease the oxidative stress and enhance synaptic plasticity, resulting in accelerated healing processes. Almost all parts of the plant have been used in the traditional system of medicine for various disorders including its use as an anticonvulsant, sexual tonic, and anti-rheumatic agent. This study is designed to evaluate the anxiolytic and antidepressant activities of the methanolic crude extract of N. procumbens (Np.Cr) based on its use in traditional medicine and presence of the phytochemical constituents. Aqueous methanolic extract of Np.Cr was prepared under reduced pressure using rotary evaporator, and different chemical constituents were identified by phytochemical screening. Light/dark exploration, elevated plus maze (EPM), and hole board tests were used to assess the anxiolytic activity, while forced swim and tail suspension tests were used to assess the antidepressant potential of the crude extract. Treatment groups treated individually with 3 different doses; i.e., 50, 100, and 200mg/kg of Np.Cr, showed a dose-dependent increase in time spent in light compartment and in open arms as well as increased number of head poking by the experimental animals. Np.Cr showed significant antidepressant potential (P < .05) as evident from marked decrease in behavioral despair. Findings of the present study assure that N. procumbens possess significant anxiolytic and antidepressant potential with the demands of further investigations to identify the active compound(s) responsible for these pharmacological effects.

Antidepressant Activities of Synthesized Benzodiazepine Analogues in Mice

Depression is a serious psychological disorder which negatively affects human feelings and actions. The use of antidepressants is the therapy of choice while treating depression. However, such drugs are associated with severe side effects. There is a need for efficient and harmless drugs. In this connection, the present study was designed to synthesize several substituted benzodiazepine derivatives and explore their antidepressant potentials in an animal model. The chalcone backbone was initially synthesized, which was then converted into several substituted benzodiazepine derivatives designated as 1-6. The synthesized compounds were identified using spectroscopic techniques. The experimental animals (mice) after acclimatation were subjected to forced swim test (FST) and tail suspension test (TST) after oral administration of the synthesized compounds to evaluate their antidepressant potentials. At the completion of the mentioned test, the animals were sacrificed to determine GABA level in their brain hippocampus. The chloro-substituent compound (2) significantly reduced the immobility time (80.81 ± 1.14 s; p < 0.001 at 1.25 mg/kg body weight and 75.68 ± 3.73 s with p < 0.001 at 2.5 mg/kg body weight dose), whereas nitro-substituent compound (5) reduced the immobility time to 118.95 ± 1.31 and 106.69 ± 3.62 s (p < 0.001), respectively, at the tested doses (FST). For control groups, the recorded immobility time recorded was 177.24 ± 1.82 s. The standard drug diazepam significantly reduced immobility time to 70.13 ± 4.12 s while imipramine reduced it to 65.45 ± 2.81 s (p < 0.001). Similarly, in the TST, the compound 2 reduced immobility time to 74.93 ± 1.14 s (p < 0.001) and 70.38 ± 1.43 s (p < 0.001), while compound 5 reduced it to 88.23 ± 1.89 s (p < 0.001) and 91.31 ± 1.73 s (p < 0.001) at the tested doses, respectively, as compared to the control group immobility time (166.13 ± 2.18 s). The compounds 1, 3, 4, and 6 showed weak antidepressant responses as compared to compounds 2 and 5. The compounds 2 and 5 also significantly enhanced the GABA level in the brain's hippocampus of experimental animals, indicating the possible involvement of GABAergic mechanism in alleviating the depression which is evident from the significant increase in mRNA levels for the α subunit of the GABAA receptors in the prefrontal cortex of mice as well. From the results, it can be concluded that compound 2 and 5 could be used as alternative drugs of depression. However, further exploration in this connection is needed in other animal models in order to confirm the observed results in this study.

Challenging the Pleiotropic Effects of Repetitive Transcranial Magnetic Stimulation in Geriatric Depression: A Multimodal Case Series Study

Although the antidepressant potential of repetitive transcranial magnetic stimulation (rTMS), the pleiotropic effects in geriatric depression (GD) are poorly investigated. We tested rTMS on depression, cognitive performance, growth/neurotrophic factors, cerebral blood flow (CBF) to transcranial Doppler sonography (TCD), and motor-evoked potentials (MEPs) to TMS in GD. In this case series study, six drug-resistant subjects (median age 68.0 years) underwent MEPs at baseline and after 3 weeks of 10 Hz rTMS on the left dorsolateral prefrontal cortex. The percentage change of serum nerve growth factor, vascular endothelial growth factor, brain-derived growth factor, insulin-like growth factor-1, and angiogenin was obtained. Assessments were performed at baseline, and at the end of rTMS; psychocognitive tests were also repeated after 1, 3, and 6 months. Chronic cerebrovascular disease was evident in five patients. No adverse/undesirable effect was reported. An improvement in mood was observed after rTMS but not at follow-up. Electrophysiological data to TMS remained unchanged, except for an increase in the right median MEP amplitude. TCD and neurotrophic/growth factors did not change. We were unable to detect a relevant impact of high-frequency rTMS on mood, cognition, cortical microcircuits, neurotrophic/growth factors, and CBF. Cerebrovascular disease and exposure to multiple pharmacological treatments might have contributed.

Chronic salmon calcitonin exerts an antidepressant effect via modulating the p38 MAPK signaling pathway.

Depression is a common recurrent psychiatric disorder with a high lifetime prevalence and suicide rate. At present, although several traditional clinical drugs such as fluoxetine and ketamine, are widely used, medications with a high efficiency and reduced side effects are of urgent need. Our group has recently reported that a single administration of salmon calcitonin (sCT) could ameliorate a depressive-like phenotype via the amylin signaling pathway in a mouse model established by chronic restraint stress (CRS). However, the molecular mechanism underlying the antidepressant effect needs to be addressed. In this study, we investigated the antidepressant potential of sCT applied chronically and its underlying mechanism. In addition, using transcriptomics, we found the MAPK signaling pathway was upregulated in the hippocampus of CRS-treated mice. Further phosphorylation levels of ERK/p38/JNK kinases were also enhanced, and sCT treatment was able only to downregulate the phosphorylation level of p38/JNK, with phosphorylated ERK level unaffected. Finally, we found that the antidepressant effect of sCT was blocked by p38 agonists rather than JNK agonists. These results provide a mechanistic explanation of the antidepressant effect of sCT, suggesting its potential for treating the depressive disorder in the clinic.

Antidepressant Potential of a Functionalized 3-Selanyl Benzo[b]Furan Compound in Mice: Focus on the Serotonergic System.

The present study investigated the antidepressant-like potential of a functionalized 3-selanyl benzo[b]furan (SeBZF) in male Swiss mice. To evaluate possible antidepressant-like actions, the compounds SeBZF1-5 (50 mg/kg, intragastric, i.g., route) were acutely screened in the tail suspension tests (TSTs). The compound 3-((4-methoxyphenyl)selanyl)-2-phenylbenzofuran (SeBZF3) was then selected. Dose-response and time-response curves revealed that SeBFZ3 exerts antidepressant-like effects in the TST (5-50 mg/kg) and forced swimming test (FST; 50 mg/kg). Additional tests demonstrated that pretreatment with receptor antagonists WAY100635 (5-HT1A; 0.1 mg/kg, subcutaneous route), ketanserin (5-HT2A/C; 1 mg/kg, intraperitoneal, i.p.), or ondansetron (5-HT3; 1 mg/kg, i.p.) blocked the SeBZF3 antidepressant-like effects (50 mg/kg) in the TST. In addition, the coadministration of subeffective doses of SeBZF3 (1 mg/kg, i.g.) and fluoxetine (a selective serotonin reuptake inhibitor; 5 mg/kg, i.p.) produced synergistic action. A high dose of SeBZF3 (300 mg/kg) did not produce oral acute toxicity. The present results provide evidence for the antidepressant-like action of SeBZF3 and its relative safety, as well as predict the possible interactions with the serotonergic system, aiding in the development of novel options to alleviate psychiatric disabilities.

Relationship between antidepressants and severity of SARS-CoV-2 Omicron infection: a retrospective cohort study using real-world data

Few studies have used real-world data to evaluate the impact of antidepressant use on the risk of developing severe outcomes after SARS-CoV-2 Omicron infection. This is a retrospective cohort study using propensity-score matching to examine the relationship between antidepressant use and COVID-19 severity. Inpatient and medication records of all adult COVID-19 patients in Hong Kong during the Omicron-predominated period were obtained. Severe clinical outcomes including intensive care unit admission and inpatient death after the first positive results of reverse transcription polymerase chain reaction as well as a composite outcome of both were studied. Cox proportional hazard models were applied to estimate the crude and adjusted hazard ratios (HR). Of 60,903 hospitalised COVID-19 patients admitted, 40,459 were included for matching, among which 3821 (9.4%) were prescribed antidepressants. The rates of intensive care unit admission, inpatient death, and the composite event were 3.9%, 25.5%, and 28.3% respectively in the unexposed group, 1.3%, 20.0%, and 21.1% respectively in the exposed group, with adjusted HR equal to 0.332 (95% CI, 0.245-0.449), 0.868 (95% CI, 0.800-0.942), and 0.786 (95% CI, 0.727-0.850) respectively. The result was generally consistent when stratified by selective serotonin reuptake inhibitors (SSRIs) and non-SSRIs. Antidepressants with functional inhibition of acid sphingomyelinase activity, specifically fluoxetine, were also negatively associated with the outcomes. The effect of antidepressants was more apparent in female and fully vaccinated COVID-19 patients. Antidepressant use was associated with a lower risk of severe COVID-19. The findings support the continuation of antidepressants in patients with COVID-19, and provide evidence for the treatment potential of antidepressants for severe COVID-19. This research was supported by Health and Medical Research Fund [grant numbers COVID190105, COVID19F03, INF-CUHK-1], Collaborative Research Fund of University Grants Committee [grant numbers C4139-20G], National Natural Science Foundation of China (NSFC) [71974165], and Group Research Scheme from The Chinese University of Hong Kong.

Resveratrol attenuates chronic social isolation stress-induced affective disorders: Involvement of NF-κB/NLRP3 axis.

Social isolation stress (SIS) is associated with affective disorders (i.e., anxiety and depression) in adults. In a preclinical study, we aimed to investigate the effects of resveratrol (RV) on the mood swings of rats exposed to SIS. Animals were randomized into six different groups, including control: healthy animals received normal saline (NS) as a vehicle; SIS + NS: SIS animals received NS; SIS + FL: SIS animals received fluoxetine (10 mg/kg/i.p.); SIS + RV20, SIS + RV40, and SIS + RV80: SIS animals received RV (20, 40, and 80 mg/kg/i.p). SIS was induced for 4weeks, then animals were treated with NS, FL, and RV for 4weeks. Rats were evaluated by the behavioral tests, including the elevated plus-maze, tail suspension test, the open field test, and forced-swimming test, for mood alterations and nuclear factor kappa B(NF-κB) levels, along with NLRP3,apoptosis-associated speck-like(ASC), and proCaspase-1 were determined in the hippocampus. Behavioral tests confirmed that exposing the animals to SIS caused anxiety and depression. The highest concentrations of NLRP3, proCaspase-1, ASC, and NF-κB, were confirmed in the SIS + NS group. Compared to FL, RV showed antidepressant potential according to the behavioral tests. In particular, the administration of RV (20, 40, and 80 mg/kg) revered the NF-κB/NLRP3 axis cascade in rats exposed to chronic SIS. Our findings revealed that RV attenuated anxiety and depression of SIS-exposed rats via regulation of NF-κB/NLRP3 signaling pathways. RV can be used as a potential anxiolytic agent and antidepressant.

5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines.

Psychedelic compounds have displayed antidepressant potential in both humans and rodents. Despite their promise, psychedelics can induce undesired effects that pose safety concerns and limit their clinical scalability. The rational development of optimized psychedelic-related medicines will require a full mechanistic understanding of how these molecules produce therapeutic effects. While the hallucinogenic properties of psychedelics are generally attributed to activation of serotonin 2A receptors (5-HT2ARs), it is currently unclear if these receptors also mediate their antidepressant effects as several nonhallucinogenic analogues of psychedelics with antidepressant-like properties have been developed. Moreover, many psychedelics exhibit promiscuous pharmacology, making it challenging to identify their primary therapeutic target(s). Here, we use a combination of pharmacological and genetic tools to demonstrate that activation of 5-HT2A receptors is essential for tryptamine-based psychedelics to produce antidepressant-like effects in rodents. Our results suggest that psychedelic tryptamines can induce hallucinogenic and therapeutic effects through activation of the same receptor.

Korean red ginseng water extract produces antidepressant-like effects through involving monoamines and brain-derived neurotrophic factor in rats

BackgroundGinseng Radix (Panax ginseng Meyer, Araliaceae) has been used medicinally to treat the brain and nervous system problems worldwide. Recent studies have revealed physiological effects that could potentially benefit cognitive performance or mood. The present study aimed to investigate the antidepressant effects of Korean red ginseng water extract (KGE) and its active component in an unpredictable chronic mild stress (UCMS)-induced animal model and elucidate the underlying mechanisms. MethodsThe antidepressant potential of the UCMS model was evaluated using the sucrose preference test and open field tests. The behavioral findings were further corroborated by the assessment of neurotransmitters and their metabolites from the prefrontal cortex and hippocampus of rats. Three doses of KGE (50, 100, and 200 mg/kg) were orally administered during the experiment. Furthermore, the mechanism underlying the antidepressant-like action of KGE was examined by measuring the levels of brain-derived neurotrophic factor (BDNF)/CREB, nuclear factor erythroid 2-related factor 2 (Nrf2), and Kelch-like ECH-associated protein 1 (Keap1) proteins in the prefrontal cortex of UCMS-exposed rats. ResultsKGE treatment normalized UCMS-induced depression-related behaviors. Neurotransmitter studies conducted after completing behavioral experiments demonstrated that KGE caused a reduction in the ratio of serotonin and dopamine, indicating a decrease in serotonin and dopamine turnover. Moreover, the expression of BDNF, Nrf2, Keap1 and AKT were markedly increased by KGE in the prefrontal cortex of depressed rats. ConclusionOur results provide evidence that KGE and its constituents exert antidepressant effects that mediate the dopaminergic and serotonergic systems and expression of BDNF protein in an animal model.

Anandamide Reuptake Inhibitor (VDM11) as a Possible Candidate for COVID-19 Associated Depression; a Combination of Network Pharmacology, Molecular Docking and In Vivo Experimental Analysis

Objective: Post-COVID 19 depression has gained much attention due to the increasing percentage of depressive symptoms reported by COVID-19 survivors. Among many factors postulated to be responsible for this depression, neuroinflammation gained the most attention. Therefore, in current work, we selected an anandamide reuptake inhibitor, VDM11, as a possible candidate for managing post-COVID depression. Methods: The role of VDM11 in attenuating neuroinflammation was established by using network pharmacology, molecular docking, and an in vivo LPS-induced depression model. Results: The results of network pharmacology revealed that among all the genes that can be targeted by VDM11, 47 genes were directly linked to the pathophysiology of depression. Additionally, on the basis of protein–protein interaction (PPI) analysis, the top 10 hub genes probably responsible for VDM11 antidepressant attribute were screened. These genes include MAPK3, TNF-α, IL-1β, IL-6, PPARG, MAPK1, CNR1, MTOR, NR3C1, and IGF1R. These genes were also enriched in GO and KEGG analysis. Molecular docking was carried out with top five hub genes screened by PPI network and KEGG analysis which showed that VDM11 interacts well with these targets. The antidepressant potential of VDM11 was also assessed by employing a LPS-induced depression model. Animals provided with VDM11 demonstrated increased exploration time and spontaneous alterations in elevated plus and Y maze models. Additionally, the level of astrocyte marker GFAP, microglia marker CD11b, and proinflammatory cytokines, including TNFα, IL-1β, and IL-6, in the hippocampus were significantly reduced by VDM11, further strengthening its role in neuroinflammation. Conclusion: VDM11, an anandamide reuptake inhibitor, might serve as a possible candidate for post-COVID depression, probably by modulating neuroinflammation. However, detailed pharmacological studies are required to validate these outcomes.

Unleashing lactoferrin's antidepressant potential through the PI3K/Akt/mTOR pathway in chronic restraint stress rats.

Depression is a widespread neuropsychiatric illness whose etiology is yet mysterious. Lactoferrin (LF), an iron-binding glycoprotein, is reported to promote neuroprotection through its role in the modulation of oxidative stress and inflammation. The objective of the present research was to evaluate the efficacy of LF against chronic restraint stress (CRS)-induced depressive behavior in rats. Depression was evidenced by a reduced grooming time in the splash test and an increased immobility time in the tail suspension test (TST) and forced swimming test (FST). This effect was also accompanied by reduced GSH and serotonin levels and elevated lipid peroxidation and corticosterone levels in the hippocampus. Additionally, an exaggerated hippocampal inflammatory response was also shown by a rise in NF-κB (p65) and TNF-α levels and a reduced IL-10 level. Moreover, CRS substantially reduced the BDNF content as well as the protein levels of PI3K, Akt, and mTOR while boosting the GSK3β content. Interestingly, LF therapy significantly improved CRS-induced behavioral and biochemical aberrations, an effect which was suppressed upon pretreatment with LY294002 (PI3K inhibitor). This suggests that the antidepressant potential of LF may be mediated through the modulation of the PI3K/Akt/mTOR signaling pathway. Furthermore, LF succeeded in restoring 5-HT and corticosterone levels, diminishing oxidative stress and ameliorating the inflammatory cascades. Therefore, and for the first time, LF might serve as a promising antidepressant drug through targeting the PI3K/Akt/mTOR pathway.