The antidepressant effect of Shexiang Baoxin Pills on myocardial infarction rats with depression may be achieved through the inhibition of the NLRP3 inflammasome pathway.

BACKGROUND: Patients with myocardial infarction (MI) frequently experience a heightened incidence of depression, thereby increasing the risk of adverse cardiovascular events. Consequently, early detection and intervention in depressive symptoms among patients with MI are imperative. Shexiang Baoxin Pills (SBP), a Chinese patent medicine employed for the treatment of MI, exhibits diverse mechanisms targeting this condition. Nevertheless, its therapeutic efficacy on postmyocardial infarction depressive symptoms remains unclear. The aim of this study is to investigate the effectiveness and mechanism of SBP in managing depression during acute myocardial infarction (AMI). METHODS: A rat model combining MI and depression was established, and the rats were randomly divided into four groups: the model (MOD) group, SBP group, Fluoxetine (FLX) group, and Sham group. After 28 days of drug intervention, cardiac function was assessed using echocardiography while behavior was evaluated through sucrose preference test (SPT), forced swimming test (FST), and open-field test (OFT). Additionally, levels of inflammatory factors in serum and hippocampus were measured along with NLRP3 inflammasome-related protein expression via Western blotting and immunofluorescence. RESULTS: SBP can enhance cardiac function in rats with AMI and depression, while significantly ameliorating depressive-like behavior. Compared to the Sham group, levels of IL-1ß, IL-18, TNF-α, and other inflammatory factors were markedly elevated in the MOD group. However, expressions of these inflammatory factors were reduced to varying degrees following treatment with SBP or FLX. Analysis of NLRP3 inflammasome-related proteins in the hippocampus revealed a significant upregulation of IL-1ß, IL-18, NLRP3, ASC, caspase-1, and GSDMD in the MOD group; conversely, these measures were significantly attenuated after SBP intervention. CONCLUSION: We have observed a significant amelioration in depression-like behavior upon SBP administration during the treatment of AMI, suggesting that this effect may be attributed to the inhibition of NLRP3-mediated pyroptosis. (The main findings are summarized in the graphical abstract in the supplementary file.).

The Black Book of Psychotropic Dosing and Monitoring.

Introduction Since the last edition of the Black Book, several innovative agents have been approved or are poised to be approved in the coming year. These include novel antidepressants, the first muscarine agonist for the treatment of schizophrenia, the first psychedelic which may be approved for the treatment of PTSD (Post Traumatic Stress Disorder), and the first disease modifying drug for the treatment of Alzheimer's disease. Three new antidepressants have come to the market in the past 18 months. The first of those, Auvelity, the combination of bupropion and dextromethorphan, takes advantage of a pharmacokinetic and pharmacodynamic synergism between the two drugs.85 Dextromethorphan has several pharmacodynamic properties including actions on the NMDA receptor and the Sigma 1 receptor, adding to the indirect norepinephrine agonist properties of bupropion. How Dextromethorphan is rapidly metabolized via the CYP2D6 isoenzyme to dextrophan that may have mu opioid agonist properties. The combination with bupropion, a CYP2D6 inhibitor, inhibits the metabolism of dextromethorphan allowing for more consistent therapeutic levels. The combination of dextromethorphan 45 mg twice per day and bupropion SR 105 mg twice daily appears to be more effective than an equivalent dose of bupropion alone both in speeding up antidepressant response and achieving remission. However, it's not clear at this time how the combination would compare with a more typical dose of bupropion of 300-450 milligrams a day range. The phase III program for Auvelity, showed that the drug was well tolerated with the most common side effects being dizziness, headache, and dry mouth.86 Another novel antidepressant agent approved in 2023 is zuranolone (Zurzuvae). Zuranolone is an oral analog of IV brexanalone, and like brexanolone, was approved for the treatment of post-partum depression.83 The advantages of zuranolone over brexanalone are many. While brexanolone is a 60-hour intravenous infusion that must be administered in a health care facility, zuranolone is a once/day oral medication that is usually taken at home. Like brexanolone, and unlike most antidepressants, zuranolone has a short course of treatment, lasting just 14 days. Zuranolone's, as does brexanolone, is thought to act primarily as allosteric modulator of the GABA-a receptors. Despite only 14 days of treatment, zuranolone produced in depression in post-partum patients a clinically and significantly meaningful improvement at day 15 and continued to day 45 or 1 month past the end of treatment. Zuranolone is a schedule IV drug. The most common side effect in clinical trials was somnolence with 36% of participants reporting this side effect vs only 6% of those on placebo.84 Other common side effects included dizziness, diarrhea and fatigue. While the FDA declined to approve zuranolone as monotherapy or as an adjunctive treatment to standard antidepressants in major depression itself, there are positive studies in non-post-partum major depression albeit with smaller effect sizes and less consistent duration of activity. It is likely that zuranolone will continue to be studied in other depressive syndromes such as depression with anxious distress. The third "new" antidepressant approved late 2023 was gepirone (Exxua). Gepirone is not exactly a new or novel antidepressant and originally sought approval in the US about 20 years ago.88 There had been two positive studies of gepirone during the original NDA application but also a number of failed, negative, or non-informative studies as well. Thus, the FDA declined to originally approve the drug. However, failed and negative trials are common with antidepressants and after much internal debate, the FDA ultimately agreed to approve the drug based on the positive trials and a relatively favorable side effect profile. Gepirone, like buspirone, is a partial agonist of the 5HT1a receptor and a 5HT2 antagonist. As such, gepirone does not tend to be associated with sexual side effects, weight gain, or sedation. The most common side effects are dizziness, nausea, and insomnia which tend to improve in many patients over time. Second generation antipsychotics (SGAs) continue to be the only class of agents [other than esketamine (Spravato)] approved in adjunctive treatment of resistant major depression. In addition to olanzapine (combined with fluoxetine; Symbyax), aripiprazole (Abilify), quetiapine (Seroquel), brexpiprazole (Rexulti), cariprazine (Vraylar) became the latest SGA to be approved in 2022.90 Adjunctive cariprazine at 1.5 mg daily was significantly more effective than adjunctive placebo in patients with MDD who had failed to achieve an adequate response with an antidepressant alone after 6 weeks of treatment. Interestingly, a 3 mg dose of cariprazine was less consistently effective.91 The major advantage of cariprazine over some of the other approved adjunctive SGA's is easy dosing, with the starting 1.5 mg dose being the optimal therapeutic dose for most people, and a lower metabolic side effect burden with most subjects having limited or no weight gain in short term trials. The most common side effect were akathisia/restlessness, fatigue, and nausea. Lumateperone (Caplyta) is also has positive phase III data in the adjunctive treatment of major depression and is expective file for approval in late 2024. Another recent major development in psychopharmacology is the reemergence of psychedelics in the treatment of psychiatric disorders. The first of these is MDMA (phenethylamine 3,4-methylenedioxymethamphetamine) assisted psychotherapy for the treatment of PTSD. A New Drug Application (NDA) was accepted by the FDA for MDMA in the treatment of PTSD in late 2023.87 Because the drug is being fast tracked as a "breakthrough" treatment by the FDA, it was expected to see approval in the summer of 2024. The phase II and III data for MDMA assisted psychotherapy in the treatment of PTSD have been quite consistent and impressive. However, independent reviews have pointed to significant deficiencies in these studies including the bias introduced because of functional unblinding; virtually all patients in psychedelic studies can guess whether they got the active drug or placebo. The functional unblinding, the lack of standardization of adjunctive psychotherapy as well as the abuse potential of MDMA, may delay an FDA approval. The typical regimen in these trials included 3 preparatory psychotherapy sessions followed by once/month dosing sessions (lasting about 8 hours) and using doses of 120-160 mg in a split dose. There were typically 3 monthly dosing sessions, each followed by 3 integrative psychotherapy sessions to help subjects process and understand their experiences during the dosing sessions. In the most recent phase 3 trials, over 70% of subjects no longer met criteria for PTDS compared to 46% of those treated with psychotherapy and placebo alone.89 The only approved medications for treating PTSD are two SSRIs, paroxetine and sertraline. These drugs effect only some dimensions of PTSD with only 20-30% achieving a remission level response with these drugs. Thus, MDMA assisted psychotherapy appears to achieve much higher levels of remission and response than has been true for the SSRIs. Since MDMA is not taken continuously, side effects from MDMA tend to be short lived. Side effects have included muscle tightness, nausea, diminished appetite, excessive sweating, feeling cold and dizziness among others. Since MDMA is currently a schedule I drug, it is likely that a rigorous Risk Evaluation Mitigation (REMs) program will be put in place and a limited number of centers and clinicians will be designated to perform MDMA assisted psychotherapy for PTSD. In addition to MDMA, psilocybin-assisted psychotherapy is in phase 3 trials for treating resistant depression but unlikely to be available before late 2025 at the earliest. An argument can be made that there has not been a truly novel antipsychotic since the introduction of clozapine in the US in 1990. All first-generation antipsychotics have been dopamine 2 antagonists and second-generation drugs have involved some ratio of 5HT2 antagonism to D2 blockade. In 2023, the FDA accepted the application of xenomaline/tropsium (KarXT) which may become the first muscarinic M1M4 agonist approved for the treatment of schizophrenia.82,83 Tropsium is added as a muscarine antagonist to block the peripheral cholinergic effects of a muscarine agonist. Xenomaline/tropsium appears to be effective in treating both positive and negative symptoms of schizophrenia. In a phase 3 study of 407 patients with schizophrenia, xenomaline/tropsium at doses of xenomaline/50 mg/tropsium 20 mg twice daily up to 125 mg/30 mg twice daily was significantly more effective than placebo in treating both and negative symptoms over 5 weeks of treatment. As would be expected, the side effect profile of xenomaline/tropsium is very different that all currently available antipsychotics. There is no risk of EPS as it is not a dopamine antagonist, and xenomaline/tropsium is not associated with significant metabolic effects. The side effects are cholinergic in nature and include constipation, dry mouth, and nausea. A decision is expected in September of 2024. The year 2023 also saw the approval of the first disease modifying drug in the treatment of Alzheimer's disease, lecanemab (Lequembi). While acetylcholinesterase inhibitors and memantine have been available for decades, these drugs modestly improve cognition in Alzheimer's disease patients and do not alter the progressive course of the illness. Lecanemab is an IV monoclonal antibody that targets the removal of beta-amyloid in the brain as well proto-fibrils that are also known to be toxic to neuronal tissue. When given early in the course of the illness, patients treated with Lecanemab showed 27% less decline on some measures of cognition and function thandid patients treated with a placebo over 18 months (about 1 and a half years). It is not known whether treatment for longer than 18 months would show lesser or greater decline over time. However, there are simulation studies that suggest that Lecanemab may modestly reduce the number of patients who progress to severe Alzheimer's disease and require institutional care. The standard dose is 10 mg/kg given via IV over one hour every 2 weeks for 18 months. Lecanemab is typically administered in an infusion center so that side effects can be monitored. The most serious side effects of Lecanemab are amyloid related imaging abnormalities (ARIA) that are associated with brain edema and microhemorrhages. ARIA can occur in up to 15% of patients. More common side effects are headache and nausea. While it remains to be seen how useful these new agents will be in clinical practice, they do represent an approach to treating neuropsychiatric disorders that are a notable departure from the pharmacotherapy of the past half century. It seems likely that some patients who have not been able to respond to or tolerate traditional pharmacotherapy will find hope in these new medications.

The Effect of Neuropsychiatric Drugs on the Oxidation-Reduction Balance in Therapy.

The effectiveness of available neuropsychiatric drugs in the era of an increasing number of patients is not sufficient, and the complexity of neuropsychiatric disease entities that are difficult to diagnose and therapeutically is increasing. Also, discoveries about the pathophysiology of neuropsychiatric diseases are promising, including those initiating a new round of innovations in the role of oxidative stress in the etiology of neuropsychiatric diseases. Oxidative stress is highly related to mental disorders, in the treatment of which the most frequently used are first- and second-generation antipsychotics, mood stabilizers, and antidepressants. Literature reports on the effect of neuropsychiatric drugs on oxidative stress are divergent. They are starting with those proving their protective effect and ending with those confirming disturbances in the oxidation-reduction balance. The presented publication reviews the state of knowledge on the role of oxidative stress in the most frequently used therapies for neuropsychiatric diseases using first- and second-generation antipsychotic drugs, i.e., haloperidol, clozapine, risperidone, olanzapine, quetiapine, or aripiprazole, mood stabilizers: lithium, carbamazepine, valproic acid, oxcarbazepine, and antidepressants: citalopram, sertraline, and venlafaxine, along with a brief pharmacological characteristic, preclinical and clinical studies effects.

Inhibition of Indoleamine 2,3-Dioxygenase Exerts Antidepressant-like Effects through Distinct Pathways in Prelimbic and Infralimbic Cortices in Rats under Intracerebroventricular Injection with Streptozotocin.

The application of intracerebroventricular injection of streptozotocin (ICV-STZ) is considered a useful animal model to mimic the onset and progression of sporadic Alzheimer's disease (sAD). In rodents, on day 7 of the experiment, the animals exhibit depression-like behaviors. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme catalyzing the conversion of tryptophan (Trp) to kynurenine (Kyn), is closely related to depression and AD. The present study aimed to investigate the pathophysiological mechanisms of preliminary depression-like behaviors in ICV-STZ rats in two distinct cerebral regions of the medial prefrontal cortex, the prelimbic cortex (PrL) and infralimbic cortex (IL), both presumably involved in AD progression in this model, with a focus on IDO-related Kyn pathways. The results showed an increased Kyn/Trp ratio in both the PrL and IL of ICV-STZ rats, but, intriguingly, abnormalities in downstream metabolic pathways were different, being associated with distinct biological effects. In the PrL, the neuroprotective branch of the Kyn pathway was attenuated, as evidenced by a decrease in the kynurenic acid (KA) level and Kyn aminotransferase II (KAT II) expression, accompanied by astrocyte alterations, such as the decrease in glial fibrillary acidic protein (GFAP)-positive cells and increase in morphological damage. In the IL, the neurotoxicogenic branch of the Kyn pathway was enhanced, as evidenced by an increase in the 3-hydroxy-kynurenine (3-HK) level and kynurenine 3-monooxygenase (KMO) expression paralleled by the overactivation of microglia, reflected by an increase in ionized calcium-binding adaptor molecule 1 (Iba1)-positive cells and cytokines with morphological alterations. Synaptic plasticity was attenuated in both subregions. Additionally, microinjection of the selective IDO inhibitor 1-Methyl-DL-tryptophan (1-MT) in the PrL or IL alleviated depression-like behaviors by reversing these different abnormalities in the PrL and IL. These results suggest that the antidepressant-like effects linked to Trp metabolism changes induced by 1-MT in the PrL and IL occur through different pathways, specifically by enhancing the neuroprotective branch in the PrL and attenuating the neurotoxicogenic branch in the IL, involving distinct glial cells.

Hippocampal PACAP signaling activation triggers a rapid antidepressant response.

BACKGROUND: The development of ketamine-like rapid antidepressants holds promise for enhancing the therapeutic efficacy of depression, but the underlying cellular and molecular mechanisms remain unclear. Implicated in depression regulation, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is investigated here to examine its role in mediating the rapid antidepressant response. METHODS: The onset of antidepressant response was assessed through depression-related behavioral paradigms. The signaling mechanism of PACAP in the hippocampal dentate gyrus (DG) was evaluated by utilizing site-directed gene knockdown, pharmacological interventions, or optogenetic manipulations. Overall, 446 mice were used for behavioral and molecular signaling testing. Mice were divided into control or experimental groups randomly in each experiment, and the experimental manipulations included: chronic paroxetine treatments (4, 9, 14 d) or a single treatment of ketamine; social defeat or lipopolysaccharides-injection induced depression models; different doses of PACAP (0.4, 2, 4 ng/site; microinjected into the hippocampal DG); pharmacological intra-DG interventions (CALM and PACAP6-38); intra-DG viral-mediated PACAP RNAi; and opotogenetics using channelrhodopsins 2 (ChR2) or endoplasmic natronomonas halorhodopsine 3.0 (eNpHR3.0). Behavioral paradigms included novelty suppressed feeding test, tail suspension test, forced swimming test, and sucrose preference test. Western blotting, ELISA, or quantitative real-time PCR (RT-PCR) analysis were used to detect the expressions of proteins/peptides or genes in the hippocampus. RESULTS: Chronic administration of the slow-onset antidepressant paroxetine resulted in an increase in hippocampal PACAP expression, and intra-DG blockade of PACAP attenuated the onset of the antidepressant response. The levels of hippocampal PACAP expression were reduced in both two distinct depression animal models and intra-DG knockdown of PACAP induced depression-like behaviors. Conversely, a single infusion of PACAP into the DG region produced a rapid and sustained antidepressant response in both normal and chronically stressed mice. Optogenetic intra-DG excitation of PACAP-expressing neurons instantly elicited antidepressant responses, while optogenetic inhibition induced depression-like behaviors. The longer optogenetic excitation/inhibition elicited the more sustained antidepressant/depression-like responses. Intra-DG PACAP infusion immediately facilitated the signaling for rapid antidepressant response by inhibiting calcium/calmodulin-dependent protein kinase II (CaMKII)-eukaryotic elongation factor 2 (eEF2) and activating the mammalian target of rapamycin (mTOR). Pre-activation of CaMKII signaling within the DG blunted PACAP-induced rapid antidepressant response as well as eEF2-mTOR-brain-derived neurotrophic factor (BDNF) signaling. Finally, acute ketamine treatment upregulated hippocampal PACAP expression, whereas intra-DG blockade of PACAP signaling attenuated ketamine's rapid antidepressant response. CONCLUSIONS: Activation of hippocampal PACAP signaling induces a rapid antidepressant response through the regulation of CaMKII inhibition-governed eEF2-mTOR-BDNF signaling.

Semaglutide Attenuates Anxious and Depressive-Like Behaviors and Reverses the Cognitive Impairment in a Type 2 Diabetes Mellitus Mouse Model Via the Microbiota-Gut-Brain Axis.

Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1ß and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety.

Antioxidant and Anti-Inflammatory Profiles of Two Mexican Heteropterys Species and Their Relevance for the Treatment of Mental Diseases: H. brachiata (L.) DC. and H. cotinifolia A. Juss. (Malpighiaceae).

Depression and anxiety are recognized as the most common mental diseases worldwide. New approaches have considered different therapeutic targets, such as oxidative stress and the inflammation process, due to their close association with the establishment and progression of mental diseases. In the present study, we evaluated the antioxidant and anti-inflammatory activities of the methanolic extracts of the plant species Heteropterys brachiata and Heteropterys cotinifolia and their main compounds, chlorogenic acid and rutin, as potential complementary therapeutic tools for the treatment of anxiety and depression, since the antidepressant and anxiolytic activities of these methanolic extracts have been shown previously. Additionally, we also evaluated their inhibitory activity on the enzyme acetylcholinesterase (AChE). Our results revealed that both species exhibited potent antioxidant activity (>90%) through the TBARS assay, while by means of the DPPH assay, only H. cotinifolia exerted potent antioxidant activity (>90%); additionally, low metal chelating activity (<40%) was detected for all samples tested in the ferrozine assay. The methanolic extracts of H. brachiata and H. cotinifolia exhibited significant anti-inflammatory activities in the TPA-induced ear edema, while only H. cotinifolia exerted significant anti-inflammatory activities in the MPO assay (>45%) and also exhibited a higher percentage of inhibition on AChE of even twice (>80%) as high as the control in concentrations of 100 and 1000 µg/mL. Thus, the potent antioxidant and inflammatory properties and the inhibition of AChE may be involved in the antidepressant activities of the species H. cotinifolia, which would be positioned as a candidate for study in drug development as an alternative in the treatment of depression.

Antidepressant Effect of Heracleum moellendorffii Extract on Behavioral Changes in Astrocyte Ablation Mouse Model of Depression by Modulating Neuroinflammation through the Inhibition of Lipocalin-2.

Astrocyte dysfunction and inflammation play a pivotal role in depression. In this study, we evaluated the antidepressant properties of Heracleum moellendorffii root extract (HME), which is traditionally used for inflammation-related diseases, in a mouse model with astrocyte depletion that resembles the prefrontal cortex pathology of depressive patients. Mice were divided into four groups, with 10 mice per group. To induce astrocyte ablation in the mice's prefrontal cortex (PFC), we used astrocytic toxin L-alpha-aminoadipic acid (L-AAA) and administered HME orally at 200 and 500 mg/kg for 22 days. We utilized the tail suspension test (TST) to assess depression-like behaviors and the open field test (OFT) to evaluate anxiety-like activities. Additionally, astrocytic and inflammatory markers in the PFC were evaluated using immunohistochemistry and ELISA. The results showed that infusion of L-AAA significantly decreased the expression of astrocytic glial fibrillary acidic protein (GFAP), which was accompanied by increased depression and anxiety-like behaviors. However, HME significantly reversed these effects by dose-dependently enhancing GFAP expression and modulating inflammatory markers, such as TNF-α, IL-6, and particularly lipocalin-2, a master proinflammatory mediator. These results imply that HME contributes to the alleviation of depression and anxiety-like behaviors by promoting astrocyte recovery and reducing neuroinflammation, especially through lipocalin-2 inhibition.

Profiling the volatile compounds of Peganum harmala L. Based on multiple sample preparation coupled with gas chromatography-mass spectrometry analysis and explored its antidepressants-like activity.

Peganum harmala L., a traditional medicinal plant in China, is renowned for its significant alkaloid content in seeds and roots exhibiting a wide range of pharmacological activities, including antidepressant, antiseptic, and antiviral. However, the volatile composition of the herb remained unclear. Apart from that, the extraction of volatile compounds through essential oil presents challenges due to the low yield and the degradation of volatile active compounds at high temperatures. This study used multiple sample preparation methods including headspace (HS), needle trap device (NTD), and liquid-liquid extraction (LLE) coupled with gas chromatography-mass spectrometry (GC-MS) to analyze the volatile compounds from the areal part of P. harmala L.. A total of 93 compounds were identified with NTD facilitating the first detection of harmine among the volatile organic compounds. Through network pharmacology and protein interaction analysis, the compounds' potential therapeutic targets of the compounds were explored, and 23 key targets were obtained (AKT1, ALB, PTGS2, MAOA, etc). KEGG pathway enrichment analysis indicated significant involvement in neuroactive ligand-receptor interactions and serotonergic synapses. The results enhanced the understanding of P. harmala's pharmacological mechanisms and supported its ethnopharmacological use.

PI3K/AKT signaling pathway: Molecular mechanisms and therapeutic potential in depression.

Depression is a serious global mental disorder. Numerous studies have found that depression may be closely related to decreased neurogenesis, neuroinflammation, neurotransmitter imbalance, and synaptic plasticity dysfunction. The pathogenesis of depression is complex and involves multiple signal transduction pathways and molecular changes. The PI3K/AKT pathway is an essential signaling pathways in neurons, which is widely expressed in emotion-related regions of the brain. Therefore, the PI3K/AKT pathway may play a moderating role in mood disorders. However, the role and mechanism of the PI3K/AKT signaling pathway in depression have not been fully described. This review systematically summarized the role of the PI3K/AKT signaling pathway in the pathogenesis of depression and discussed its potential in the treatment of depression. This will help in the treatment of depression and the development of antidepressants.

Therapeutic potential of cannabidiol in depression.

Major depressive disorder (MDD) is a widespread and debilitating condition affecting a significant portion of the global population. Traditional treatment for MDD has primarily involved drugs that increase brain monoamines by inhibiting their uptake or metabolism, which is the basis for the monoaminergic hypothesis of depression. However, these treatments are only partially effective, with many patients experiencing delayed responses, residual symptoms, or complete non-response, rendering the current view of the hypothesis as reductionist. Cannabidiol (CBD) has shown promising results in preclinical models and human studies. Its mechanism is not well-understood, but may involve monoamine and endocannabinoid signaling, control of neuroinflammation and enhanced neuroplasticity. This chapter will explore CBD's effects in preclinical and clinical studies, its molecular mechanisms, and its potential as a treatment for MDD.

Study on the antidepressant activity of (2R,6R; 2S,6S)-Hydroxynorketamine (HNK) and its derivatives.

OBJECTIVE: This study mainly explores (2R,6R; 2S,6S)-HNK and its compounds whether there are antidepressant effects. METHODS: Four HNK compounds were obtained from 2-(Chlorophenyl) Cyclopentylmethanone. Forced swimming test, locomotor sensitization test, and conditioned location preference test were used to screen the antidepressant activity of the synthesized target compounds. RESULTS: In the case of 10 mg HNK treatment, compared with saline, the immobile time of mice in the HNK group, I5 group and I6 group at 1 h and 7 days had statistical significance. In the case of 10 mg HNK treatment, compared with saline, the immobile time of compound C and D groups in the glass cylinder area was significantly different. In the locomotor sensitization test, the movement distance of compound C and D groups on day 15 and day 7 mice increased significantly compared with the first day. In the conditioned place preference experiment, compound C and compound D induced conditioned place preference in mice compared with the Veh group. CONCLUSION: The results of the forced swimming test, locomotor sensitization test, and conditioned location preference test showed that compounds C and D may have certain anti-depressant activity. However, HNK exerts a rapid and significant antidepressant effect within 1 week, but the duration is short.

Development of heterocyclic-based frameworks as potential scaffold of 5-HT1A receptor agonist and future perspectives: A review.

As a subtype of the 5-hydroxytryptamine (5-HT) receptor, 5-HT1A receptors are involved in the pathological process of psychiatric disorders and is an important target for antidepressants. The research groups focus on these area have tried to design novel compounds to alleviate depression by targeting 5-HT1A receptor. The heterocyclic structures is an important scaffold to enhance the antidepressant activity of ligands, including piperazine, piperidine, benzothiazole, and pyrrolidone. The current review highlights the function and significance of nitrogen-based heterocyclics 5-HT1AR represented by piperazine, piperidine, benzothiazole, and pyrrolidone in the development of antidepressant.

Antidepressant-like Effects of Chinese Quince (Chaenomeles sinensis) Fruit Based on In Vivo and Molecular Docking Studies.

In this study, we examined the potential antidepressant-like effects of Chinese quince fruit extract (Chaenomeles sinensis fruit extract, CSFE) in an in vivo model induced by repeated injection of corticosterone (CORT)-induced depression. HPLC analysis determined that chlorogenic acid (CGA), neo-chlorogenic acid (neo-CGA), and rutin (RT) compounds were major constituents in CSFE. Male ICR mice (5 weeks old) were orally administered various doses (30, 100, and 300 mg/kg) of CSFE and selegiline (10 mg/kg), a monoamine oxidase B (MAO-B) inhibitor, as a positive control following daily intraperitoneal injections of CORT (40 mg/kg) for 21 days. In our results, mice treated with CSFE exhibited significant improvements in depressive-like behaviors induced by CORT. This was evidenced by reduced immobility times in the tail suspension test and forced swim test, as well as increased step-through latency times in the passive avoidance test. Indeed, mice treated with CSFE also exhibited a significant decrease in anxiety-like behaviors as measured by the elevated plus maze test. Moreover, molecular docking analysis indicated that CGA and neo-CGA from CSFE had stronger binding to the active site of MAO-B. Our results indicate that CSFE has potential antidepressant effects in a mouse model of repeated injections of CORT-induced depression.

Exploring the potential of drug repurposing for treating depression.

Researchers are interested in drug repurposing or drug repositioning of existing pharmaceuticals because of rising costs and slower rates of new medication development. Other investigations that authorized these treatments used data from experimental research and off-label drug use. More research into the causes of depression could lead to more effective pharmaceutical repurposing efforts. In addition to the loss of neurotransmitters like serotonin and adrenaline, inflammation, inadequate blood flow, and neurotoxins are now thought to be plausible mechanisms. Because of these other mechanisms, repurposing drugs has resulted for treatment-resistant depression. This chapter focuses on therapeutic alternatives and their effectiveness in drug repositioning. Atypical antipsychotics, central nervous system stimulants, and neurotransmitter antagonists have investigated for possible repurposing. Nonetheless, extensive research is required to ensure their formulation, effectiveness, and regulatory compliance.

[Resolvin E1 as a potential lead for the treatment of depression].

Typical monoamine-based antidepressants have significant limitations, including a time lag for therapeutic response and low efficacy (more than one-third of depressed patients fail to respond to multiple antidepressant medications and are considered treatment-resistant). Conversely, ketamine, an N-methyl-D-aspartate receptor antagonist, exhibits rapid and sustained antidepressant actions in patients with treatment-resistant depression. However, clinical use of ketamine is limited due to its serious side effects. Thus, there is a significant need to develop novel ketamine-like antidepressants with fewer side effects. We previously demonstrated that intracerebroventricular infusion of resolvins (RvD1, RvD2, RvE1, RvE2, and RvE3), specialized pro-resolving lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, produce antidepressant-like effects in mouse models of depression. Among resolvins, RvE1 produces the most potent antidepressant-like effects likely via ChemR23 in several mouse models of depression. Local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) also produces antidepressant-like effects, suggesting that these brain regions are sites of action of RvE1. Additionally, intranasal (i.n.) administration of RvE1 produces antidepressant-like effects through mechanisms similar to ketamine: activity-dependent release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and subsequent mechanistic target of rapamycin complex 1 (mTORC1) activation in the mPFC play a crucial role in the rapid and sustained antidepressant-like actions of i.n. RvE1. Moreover, the antidepressant-like effects of i.n. RvE1 require BDNF and VEGF release, but not mTORC1 activation, in the dorsal DG. These findings suggest that RvE1 can be a promising lead for a novel rapid-acting antidepressant.

[Up-to-Date on clinical and preclinical studies of psilocybin therapy].

Major Depressive Disorder (MDD) poses a significant global health burden, with 30-40% patients developing resistance to standard clinical antidepressants, such as selective serotonin reuptake inhibitors and tricyclic antidepressants. In 2016, Carhart-Harris and colleagues reported that psilocybin, the hallucinogenic compound derived from magic mushrooms, exhibits rapid and enduring antidepressant effects in patients with treatment-resistant depression. Subsequent clinical studies have found the therapeutic potential of psilocybin in MDD, depressive episode in bipolar disorder, anorexia, and drug addiction. In 2018 and 2019, the U.S. Food and Drug Administration designated psilocybin as a "breakthrough medicine" for treatment-resistant depression and MDD, respectively. Notably, the side effects of psilocybin are limited to transient and mild issues, such as headache and fatigue, suggesting its safety. In 2023, we published a review on the role of serotonin 5-HT2A receptors in the antidepressant effects of serotonergic psychedelics (Nihon Yakurigaku Zasshi, Volume 158, Issue 3, Page 229-232). Here, we present our study alongside the latest clinical and preclinical research on the antidepressant effects of psilocybin and provide an overview of the potential and issues related to psilocybin therapy.

[Strategy for the development of small-molecule antidepressant targeting PAC1 receptor].

Major depressive disorder (MDD) is a psychiatric disorder that affects more than 300 million people worldwide and has a serious impact on society. Conventional antidepressants targeting monoamines in the brain based on the monoamine hypothesis are known to take a prolonged time to be effective or less effective in 30% of MDD patients. Hence, there is a need to develop antidepressants that are effective against treatment-resistant depression and have a new mechanism different from the monoamine hypothesis. An increasing number of research groups including us have been establishing that pituitary adenylate cyclase-activating polypeptide (PACAP) and one of its receptors, PAC1 receptor, are closely related to the etiology of stress-related diseases such as MDD. Therefore, it is strongly suggested that the PAC1 receptor is a promising target in the treatment of psychiatric disorders. We developed a novel, non-peptidic, small-molecule, high-affinity PAC1 receptor antagonists and conducted behavioral pharmacology experiments in mice to characterize a novel PAC1 receptor antagonist as a new option for MDD therapy. The results show that our novel PAC1 receptor antagonist has the potential to be a new antidepressant with a high safety profile. In this review, we would like to present the background of developing our novel PAC1 receptor antagonist and its effects on mouse models of acute stress.

Deciphering the gut microbiota's (Coprococcus and Subdoligranulum) impact on depression: Network pharmacology and molecular dynamics simulation.

Depression, a prevalent mental health condition, significantly impacts global mental impairment rates. While antidepressants are commonly used, treatment-resistant depression (TRD) poses a challenge. Emerging research highlights the role of the gut microbiota in depression through the gut-brain axis. This study identifies key genes associated with depression influenced by specific gut microbiota, Coprococcus and Subdoligranulum. Using bioinformatics tools, potential targets were elucidated, and molecular docking studies were performed. Furthermore, gene expression analysis identified hub-genes related to depression, intersecting with metabolite targets. Protein-protein interaction analysis revealed pivotal targets such as PTGS2 and MMP9. Molecular docking demonstrated 3-Indolepropionic acid's superior affinity over (R)-3-(4-Hydroxyphenyl)lactate. Physicochemical properties and toxicity profiles were compared, suggesting favorable attributes for 3-Indolepropionic acid. Molecular dynamics simulations confirmed stability and interactions of compounds with target proteins. This comprehensive approach sheds light on the complex interplay between gut microbiota, genes, and depression, emphasizing the potential for microbiota-targeted interventions in mental health management.

New insights about the antidepressant-like effects of riparin A in a chronic murine model of depression.

Riparin A is a synthetic form of natural riparins. Acute scale studies that take into consideration the structure-activity relationship have shown preliminary evidence of antidepressant and anxiolytic effects of riparin A, similar to that already known for other riparins. However, for better pharmacological characterization of this new compound, further studies are required. The aim of this work was to evaluate the effect of chronic treatment with riparin A (10 mg/kg; intraperitoneally) on depressive-like behavior in the forced swimming test and tail suspension test, as well as the reduction of anhedonia in the sucrose preference test, and on anxiety-like behavior in the open field and elevated plus maze apparatus, triggered in rats previously subjected to unpredictable chronic mild stress by 4 weeks. In addition, a pentobarbital-induced sleep time test was also used. Riparin A reduced the duration of immobility in both the forced swimming test and tail suspension test, as well as attenuated the anhedonia in the sucrose preference test. Furthermore, riparin A appears to produce anxiolytic effects in rats exposed to an open field and elevated plus maze, while increasing the alertness/vigilance in rats submitted to pentobarbital-induced sleep time test, without altering their locomotor integrity. Our results suggest that chronic riparin A appears to be a potential pharmacological target for new studies on the control of depression- and anxiety-like behaviors in stressed rats.