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ETHNOPHARMACOLOGICAL RELEVANCE: Modified Danzhi Xiaoyao San (MDXS) is an effective clinical prescription for depression in China, which was deprived of Danzhi Xiaoyao San in the Ming Dynasty. MDSX has significant implications for the development of new antidepressants, but its pharmacological mechanism has been rarely studied. AIM OF THE STUDY: To reveal the active components and molecular mechanism of MDXS in treating depression through network pharmacology and experimental verification in vivo and in vitro. MATERIALS AND METHODS: UPLC-Q-TOF-MS/MS was used to identify the chemical components in the MDXS freeze-dried powder, drug-containing serum, and cerebrospinal fluid (CSF). Based on the analysis of prototype components in the CSF, the major constituents, potential therapeutic targets and possible pharmacological mechanisms of MDXS in treating depression were investigated using network pharmacological and molecular docking. Then corticosterone (CORT)-induced mice model of depression was established to investigate the antidepressant effects of MDXS. HT22 cells were cultured to verify the neuroprotective effects and core targets of the active components. RESULTS: There were 81 compounds in MDXS freeze-dried powder, 36 prototype components in serum, and 13 prototype components in CSF were identified, respectively. Network pharmacology analysis showed that these 13 prototype components in the CSF shared 190 common targets with depression, which were mainly enriched in MAPK and PI3K/AKT signaling pathways. PPI analysis suggested that AKT1 and MAPK1 (ERK1/2) were the core targets. Molecular docking revealed that azelaic acid (AA), senkyunolide A (SA), atractylenolide III (ATIII), and tokinolide B (TB) had the highest binding energy with AKT1 and MAPK1. Animal experiments verified that MDXS could reverse CORT-induced depression-like behaviors, improve synaptic plasticity, alleviate neuronal injury in hippocampal CA3 regions, and up-regulate the protein expression of p-ERK1/2 and p-AKT. In HT22 cells, azelaic acid, senkyunolide A, and atractylenolide III significantly protected the cell injury caused by CORT, and up-regulated the protein levels of p-ERK1/2 and p-AKT. CONCLUSIONS: These results suggested that MDXS may exert antidepressant effects partially through azelaic acid, senkyunolide A, and atractylenolide III targeting ERK1/2 and AKT.
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Antidepresivos , Depresión , Medicamentos Herbarios Chinos , Simulación del Acoplamiento Molecular , Farmacología en Red , Animales , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Ratones , Masculino , Línea Celular , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Corticosterona/sangre , Espectrometría de Masas en Tándem , Conducta Animal/efectos de los fármacosRESUMEN
The mechanism of action of selective serotonin reuptake inhibitors (SSRI) is still not properly established. It is essential to consider their positive and negative side effects before prescribing. In this article, we describe several of these side effects in the context of common pathologies and clinical situations. We discuss their cardioprotective effect and their role in the functional recovery of patients following stroke. We recall the increase in the risk of bleeding when prescribing SSRI concomitantly with antiaggregating and anticoagulant treatments. Prescribing SSRI also increases the risk of fracture and the frequency of hyponatremia. In the context of COPD, the effects of SSRI are more difficult to establish.
Le mécanisme d'action des antidépresseurs inhibiteurs sélectifs de la recapture de la sérotonine (ISRS) n'est toujours pas formellement établi. Il est essentiel de prendre en compte leurs effets secondaires positifs et négatifs pour leur prescription. Dans cet article, nous décrivons plusieurs de ces effets dans le contexte de pathologies et situations cliniques courantes. Nous abordons leur effet cardioprotecteur ainsi que leur rôle dans la récupération fonctionnelle des patients à la suite des accidents vasculaires cérébraux. Nous rappelons la majoration du risque hémorragique lors de la prescription d'ISRS en concomitance de traitements antiagrégants et anticoagulants. La prescription d'ISRS augmente également le risque fracturaire et la fréquence d'une hyponatrémie. Dans le contexte de la bronchopneumopathie chronique obstructive, les effets d'un ISRS sont plus difficiles à établir.
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Inhibidores Selectivos de la Recaptación de Serotonina , Humanos , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Antidepresivos/efectos adversos , Antidepresivos/farmacología , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/inducido químicamente , Hemorragia/inducido químicamente , Fracturas Óseas/prevención & control , Fracturas Óseas/inducido químicamenteRESUMEN
The L-type Ca2+ channel (LTCC, also known as Cav1,2) is involved in the regulation of key neuronal functions, such as dendritic information integration, cell survival, and neuronal gene expression. Clinical studies have shown an association between L-type calcium channels and the onset of depression, although the precise mechanisms remain unclear. The development of depression results from a combination of environmental and genetic factors. DNA methylation, a significant epigenetic modification, plays a regulatory role in the pathogenesis of psychiatric disorders such as posttraumatic stress disorder (PTSD), depression, and autism. In our study, we observed reduced Dnmt3a expression levels in the hippocampal DG region of mice with LPS-induced depression compared to control mice. The antidepressant Venlafaxine was able to increase Dnmt3a expression levels. Conversely, Bay K 8644, an agonist of the L-type Ca2+ channel, partially ameliorated depression-like behaviors but did not elevate Dnmt3a expression levels. Furthermore, when we manipulated DNA methylation levels during Bay K 8644 intervention in depression-like models, we found that enhancing the expression of Dnmt3a could improve LPS-induced depression/anxiety-like behaviors, while inhibiting DNA methylation exacerbated anxiety-like behaviors, the combined use of BAY K 8644 and L-methionine can better improve depressive-like behavior. These findings indicate that DNA methylation plays a role in the regulation of depression-like behaviors by the L-type Ca2+ channel, and further research is needed to elucidate the interactions between DNA methylation and L-type Ca2+ channels.
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Ácido 3-piridinacarboxílico, 1,4-dihidro-2,6-dimetil-5-nitro-4-(2-(trifluorometil)fenil)-, Éster Metílico , Agonistas de los Canales de Calcio , Canales de Calcio Tipo L , Metilación de ADN , ADN Metiltransferasa 3A , Depresión , Metionina , Animales , Canales de Calcio Tipo L/metabolismo , Canales de Calcio Tipo L/efectos de los fármacos , Metionina/farmacología , Masculino , Depresión/tratamiento farmacológico , Depresión/metabolismo , Ratones , Agonistas de los Canales de Calcio/farmacología , Metilación de ADN/efectos de los fármacos , Ácido 3-piridinacarboxílico, 1,4-dihidro-2,6-dimetil-5-nitro-4-(2-(trifluorometil)fenil)-, Éster Metílico/farmacología , Ratones Endogámicos C57BL , Antidepresivos/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Lipopolisacáridos/farmacología , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Rapid-acting antidepressants (RAADs), including dissociative anesthetics, psychedelics, and empathogens, elicit rapid and sustained therapeutic improvements in psychiatric disorders by purportedly modulating neuroplasticity, neurotransmission, and immunity. These outcomes may be mediated by, or result in, an acute and/or sustained entrainment of epigenetic processes, which remodel chromatin structure and alter DNA accessibility to regulate gene expression. METHODS: In this perspective, we present an overview of the known mechanisms, knowledge gaps, and future directions surrounding the epigenetic effects of RAADs, with a focus on the regulation of stress-responsive DNA and brain regions, and on the comparison with conventional antidepressants. MAIN BODY: Preliminary correlative evidence indicates that administration of RAADs is accompanied by epigenetic effects which are similar to those elicited by conventional antidepressants. These include changes in DNA methylation, post-translational modifications of histones, and differential regulation of non-coding RNAs in stress-responsive chromatin areas involved in neurotrophism, neurotransmission, and immunomodulation, in stress-responsive brain regions. Whether these epigenetic changes causally contribute to the therapeutic effects of RAADs, are a consequence thereof, or are unrelated, remains unknown. Moreover, the potential cell type-specificity and mechanisms involved are yet to be fully elucidated. Candidate mechanisms include neuronal activity- and serotonin and Tropomyosine Receptor Kinase B (TRKB) signaling-mediated epigenetic changes, and direct interaction with DNA, histones, or chromatin remodeling complexes. CONCLUSION: Correlative evidence suggests that epigenetic changes induced by RAADs accompany therapeutic and side effects, although causation, mechanisms, and cell type-specificity remain largely unknown. Addressing these research gaps may lead to the development of novel neuroepigenetics-based precision therapeutics.
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Antidepresivos , Metilación de ADN , Epigénesis Genética , Epigénesis Genética/efectos de los fármacos , Humanos , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Metilación de ADN/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Animales , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/genética , Histonas/metabolismo , Estrés Psicológico/genéticaRESUMEN
Depression is a debilitating mental illness that severely threatens millions of individuals and public health. Because of the multifactorial etiologies, there is currently no cure for depression; thus, it is urgently imperative to find alternative antidepressants and strategies. Growing evidence underscores the prominent role of oxidative stress as key pathological hallmarks of depression, making oxidative stress a potential therapeutic target. In this study, we report a N-doped carbon dot nanozyme (CDzyme) with excellent antioxidant capacity for treating depression by remodeling redox homeostasis and gut microbiota. The CDzymes prepared via microwave-assisted fast polymerization of histidine and glucose exhibit superior biocompatibility. Benefiting from the unique structure, CDzymes can provide abundant electrons, hydrogen atoms, and protons for reducing reactions, as well as catalytic sites to mimic redox enzymes. These mechanisms collaborating endow CDzymes with broad-spectrum antioxidant capacity to scavenge reactive oxygen and nitrogen species (â¢OH, O2-â¢, H2O2, ONOO-), and oxygen/nitrogen centered free radicals. A depression animal model was established by chronic unpredictable mild stress (CUMS) to evaluate the therapeutic efficacy of CDzymes from the behavioral, physiological, and biochemical index and intestinal flora assessments. CDzymes can remarkably improve depression-like behaviors and key neurotransmitters produced in hippocampus tissues and restore the gut microbiota compositions and the amino acid metabolic functions, proving the potential in treating depression through the intestinal-brain axis system. This study will facilitate the development of intestinal flora dysbiosis nanomedicines and treatment strategies for depression and other oxidative stress related multifactorial diseases.
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Antioxidantes , Carbono , Depresión , Microbioma Gastrointestinal , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Carbono/química , Carbono/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Depresión/tratamiento farmacológico , Ratones , Estrés Oxidativo/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , Masculino , Puntos Cuánticos/química , Antidepresivos/farmacología , Antidepresivos/químicaRESUMEN
Depression is a prevalent and debilitating mental disorder that affects millions worldwide. Current treatments, such as antidepressants targeting the serotonergic system, have limitations, including delayed onset of action and high rates of treatment resistance, necessitating novel therapeutic strategies. Ginsenoside Rc (G-Rc) has shown potential anti-inflammatory and neuroprotective effects, but its antidepressant properties remain unexplored. This study investigated the antidepressant effects of G-Rc in an L-alpha-aminoadipic acid (L-AAA)-induced mouse model of depression, which mimics the astrocytic pathology and neuroinflammation observed in major depressive disorder. Mice were administered G-Rc, vehicle, or imipramine orally after L-AAA injection into the prefrontal cortex. G-Rc significantly reduced the immobility time in forced swimming and tail suspension tests compared to vehicle treatment, with more pronounced effects than imipramine. It also attenuated the expression of pro-inflammatory cytokines (TNF-α, IL-6, TGF-ß, lipocalin-2) and alleviated astrocytic degeneration, as indicated by increased GFAP and decreased IBA-1 levels. Additionally, G-Rc modulated apoptosis-related proteins, decreasing caspase-3 and increasing Bcl-2 levels compared to the L-AAA-treated group. These findings suggest that G-Rc exerts antidepressant effects by regulating neuroinflammation, astrocyte-microglia crosstalk, and apoptotic pathways in the prefrontal cortex, highlighting its potential as a novel therapeutic agent for depression.
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Ácido 2-Aminoadípico , Antidepresivos , Astrocitos , Ginsenósidos , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ratones , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Ginsenósidos/farmacología , Masculino , Ácido 2-Aminoadípico/farmacología , Depresión/tratamiento farmacológico , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Modelos Animales de Enfermedad , Citocinas/metabolismo , Ratones Endogámicos C57BL , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Apoptosis/efectos de los fármacosRESUMEN
Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, associated with substantial burden and large economical costs. Notwithstanding various conventional antidepressant treatment options, a large portion of depressed people (ca. 30%) fails to respond to first-line treatment, resulting in treatment-resistant depression (TRD). Although non-response to multiple antidepressant interventions is a common outcome, a consensus definition of TRD is not yet available. In practice, TRD is applied when two or more successive treatments with different antidepressants are not working. The last decade's intense research into new medicines for TRD has led to two developments, using typical or serotonergic (psilocybin, ayahuasca) and atypical (glutamatergic) psychedelics (ketamine, esketamine). Both approaches, although via different entrance mechanism, exhibit a fast onset but also long-lasting antidepressant effect far beyond the biological presence of the drug in the body, strongly indicating that downstream mechanisms activated by signaling cascades in the brain are involved. The present chapter describes the clinical development of psilocybin and esketamine for TRD and discusses the problems involved in the use of a proper placebo because of the psychotomimetic (psilocybin) or dissociative (ketamine) effects that interfere with performing "blind" studies. Nevertheless, intranasal esketamine was developed and approved for TRD, whereas psilocybin has shown positive results. Adverse effects and tolerability of both drugs in the dose ranges used are generally acceptable. The emergence of anti-TRD medicines for treatment of a very severe disease is a breakthrough in psychiatry.
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Antidepresivos , Trastorno Depresivo Resistente al Tratamiento , Alucinógenos , Ketamina , Psilocibina , Humanos , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Alucinógenos/uso terapéutico , Alucinógenos/efectos adversos , Alucinógenos/farmacología , Ketamina/uso terapéutico , Ketamina/efectos adversos , Psilocibina/uso terapéutico , Psilocibina/efectos adversos , Psilocibina/farmacología , Antidepresivos/uso terapéutico , Antidepresivos/efectos adversos , Antidepresivos/farmacología , Trastorno Depresivo Mayor/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Major depressive disorder (MDD) is a mental health disorder associated with cognitive impairment, dysregulated appetite, fatigue, insomnia or hypersomnia, and severe mood changes that significantly impact the ability of the affected individual to perform day-to-day tasks, leading to suicide in the worst-case scenario. As MDD is becoming more prevalent, affecting roughly 300 million individuals worldwide, its treatment has become a major point of interest. Antidepressants acting as selective serotonin reuptake inhibitors (SSRIs) are currently used as the first line of treatment for MDD. Other antidepressants currently used for the treatment of MDD include the serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). However, although effective in alleviating symptoms of MDD, most antidepressants require weeks or even months of regular administration prior to eliciting a rational clinical effect. Owing to the strong evidence showing a relationship between neural plasticity, neurogenesis, and MDD, researchers have also looked at the possibility of using treatment modalities that target these processes in an attempt to improve clinical outcome. The overarching aim of this chapter is to highlight the role of neural plasticity and neurogenesis in the pathophysiology of MDD and discuss the most recently studied treatment strategies that target these processes by presenting supporting evidence from both animal and human studies.
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Antidepresivos , Trastorno Depresivo Mayor , Neurogénesis , Plasticidad Neuronal , Humanos , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/fisiopatología , Neurogénesis/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Antidepresivos/uso terapéutico , Antidepresivos/farmacología , Animales , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
Phenylpiracetam (PP) is a nootropic drug with additional pharmacological effects, including anxiolytic, antiasthenic, antidepressant, anti-inflammatory and anticonvulsant effects. The paper presents the results of an analysis of experimental and clinical studies, which indicate the prospects for the use of PP in cerebral ischemia, neurodegenerative pathologies, epilepsy, asthenia, and mental disorders. The adaptogenic properties and mitochondrial protective effect of PP are considered, assessments of the possible effect of PP on neurotransmitter systems, regulation of carbohydrate and fat metabolism with the prospects for the use of PP in patients with metabolic syndrome.
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Anticonvulsivantes , Humanos , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/farmacología , Nootrópicos/uso terapéutico , Nootrópicos/farmacología , Pirrolidinonas/uso terapéutico , Pirrolidinonas/farmacología , Epilepsia/tratamiento farmacológico , Antidepresivos/uso terapéutico , Antidepresivos/farmacología , Animales , Astenia/tratamiento farmacológico , Trastornos Mentales/tratamiento farmacológico , Ansiolíticos/uso terapéutico , Ansiolíticos/farmacología , Piracetam/análogos & derivadosRESUMEN
The root of Millettia pulchra (YLS) has been traditionally used as a folk medicine for the treatment of depression and insomnia in the Zhuang nationality of China, and its polysaccharides have potential antidepressant effect. In this study, a novel homogeneous polysaccharide (YLP-1) was purified from the crude polysaccharides of YLS, and it is mainly composed of glucose, arabinose and mannose with molar ratio of 87.25%, 10.77%, and 1.98%, respectively. YLP-1 is a novel α-glucan with the backbone of 1,4-Glcp and branched at C6 of 1,4,6-Glcp to combine 1,4-Manp and 1,5-Araf. The microstructure of YLP-1 displayed a uniform ellipsoidal-like chain morphology and dispersed uniformly in solution. YLP-1 effectively ameliorated depression-like ethological behaviors and restored the decreased catecholamine levels in chronic variable stress (CVS)-induced depression rats. Additionally, it significantly improved the disturbance of gut microbiota induced by CVS stimuli, particularly affecting bacteria that produce short-chain fatty acids (SCFAs), such as bacteria species Lactobacillus spp.. In vitro fermentation study further confirmed that YLP-1 intake could promote SCFAs production by Lactobacillus spp. YLP-1 also mitigated the disruption of tryptophan metabolites in urine and serum. These findings provide evidences for the further development of YLP-1 as a macromolecular antidepressant drug.
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Antidepresivos , Ácidos Grasos Volátiles , Microbioma Gastrointestinal , Millettia , Polisacáridos , Triptófano , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Antidepresivos/farmacología , Antidepresivos/química , Masculino , Ratas , Polisacáridos/farmacología , Polisacáridos/química , Millettia/química , Triptófano/metabolismo , Ácidos Grasos Volátiles/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Ratas Sprague-DawleyRESUMEN
The main hurdles with current therapies for major depressive disorder (MDD) include lack of efficacy, therapeutic latency, and adverse drug reactions. Add-on therapy to conventional antidepressants may result in better therapeutic outcomes to overcome these obstacles. Sarcosine (N-methyl glycine), an endogenous amino acid that acts by modulating the NMDA receptor, is available as a dietary supplement. So, the present study was planned to evaluate the efficacy and safety of add-on sarcosine to SSRIs in MDD. In the present randomized, double-blind clinical trial (NCT04975100), 60 eligible participants with MDD were randomly assigned to either the test group (SSRI + sarcosine) or the control group (SSRI + placebo). Clinical and biochemical parameters like MADRS, CGI, serum BDNF, and serum glycine were assessed at baseline and eight weeks. The mean reduction in MADRS score was significant in both the control (-8.7, 95% CI: -11.0 to -6.4, p < 0.001) and the test group (-13.3, 95% CI: -14.9 to -11.7, p < 0.001), but the change in the test group was significantly greater (-4.6, 95% CI: -7.5 to -1.7, p = 0.003). The test group had a significantly higher response rate (p = 0.007) and remission rate (p = 0.038) compared to the control group. There was a significant increase in serum BDNF in both groups; however, the change in the test group was significantly higher than in the control group (p = 0.041). Similarly, the test group had a significantly higher increase in serum glycine than the control group (p < 0.001). Sarcosine may be considered an efficacious and safe add-on therapy to standard SSRIs in the management of MDD. ClinicalTrial.gov IdentifierNCT04975100.
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Factor Neurotrófico Derivado del Encéfalo , Trastorno Depresivo Mayor , Quimioterapia Combinada , Sarcosina , Inhibidores Selectivos de la Recaptación de Serotonina , Humanos , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/sangre , Masculino , Femenino , Adulto , Sarcosina/farmacología , Sarcosina/sangre , Sarcosina/administración & dosificación , Método Doble Ciego , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Persona de Mediana Edad , Factor Neurotrófico Derivado del Encéfalo/sangre , Adulto Joven , Evaluación de Resultado en la Atención de Salud , Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Antidepresivos/farmacologíaRESUMEN
Vortioxetine is a novel multimodal antidepressant, but its precise efficacy and dose-response relationship for treating different symptoms in major depressive disorder (MDD) is still unclear. This umbrella review aims to assess the effectiveness, tolerability, and dose-response relationship of vortioxetine across a comprehensive range of clinical features in adults with MDD, including cognition, depression, anxiety, quality of life, and side effects. We meticulously searched eight electronic databases and included systematic reviews (SRs) and meta-analyses (MAs) of vortioxetine. The methodological quality of each included SR was independently assessed using the AMSTAR2 tool. To evaluate the credibility of the evidence, we utilized the GRADE framework and the Ioannidis criteria. In total, 35 SRs with 278 MAs met the inclusion criteria and based on these studies we performed 56 MAs of interest. While vortioxetine has been consistently shown to have positive effects on various domains, the evidence regarding cognitive performance and depression symptoms is notably robust compared to placebo, despite of relatively overall low quality of evidence. Finally, a dose-response relationship was observed across all categories within the treatment range of 5-20 mg/d and a dosage of vortioxetine 20 mg/d is recommended for adult MDD patients to achieve full functional recovery.
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Antidepresivos , Trastorno Depresivo Mayor , Relación Dosis-Respuesta a Droga , Vortioxetina , Vortioxetina/farmacología , Vortioxetina/administración & dosificación , Humanos , Trastorno Depresivo Mayor/tratamiento farmacológico , Antidepresivos/farmacología , Antidepresivos/administración & dosificación , Calidad de VidaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Jiawei-Xiaoyao Pill (JWX), a classic formula in traditional Chinese medicine, is derived from Xiaoyao Pill by adding significant amounts of Gardeniae Fructus (GF) and Moutan Cortex (MC). It is frequently used for the treatment of depression. JWX has been demonstrated to uniquely elicit rapid antidepressant-like effects within the prescribed dosage range. To date, GF has been shown to have rapid antidepressant-like effects, but a much higher dose is required than its proportion in JWX. It is assumed that the synergism of GF with a minimum number of other herbs in JWX serves as a refined formula that exerts these rapid antidepressant-like effects. Identification of a refined formula is important for prioritizing the herbs and ingredients to optimize the quality control of JWX. However, such a refined formula for JWX has not been identified yet. AIM OF THE STUDY: Here we aimed to identify a refined formula derived from JWX for optimized rapid antidepressant-like effects. Since the neuroinflammation mechanism involving in depression treatment has not been previously investigated for JWX, we tested the mechanism for both JWX and the refined formula. MATERIALS AND METHODS: Individual herbs (MC; ASR, Angelica Sinensis Radix; Bupleuri Radix; Paeonia Radix Alba) that show antidepressant-like responses were mixed with GF at the proportional dosage in JWX to identify the refined formula. Rapid antidepressant-like effects were assessed by using NSF (Novelty Suppressed Feeding Test) and other behavioral tests following a single administration. The identified formula was further tested in a lipopolysaccharide (LPS)-induced depressive model, and the molecular signaling mechanisms were investigated using Western blot analysis, immunofluorescence, and pharmacological inhibition of mTOR signaling. Scopolamine (Scop) was used as a positive control for induction of rapid antidepressant effects. RESULTS: A combination of GF, MC and ASR (GMA) at their dosages proportional to JWX induced behavioral signs of rapid antidepressant-like responses in both normal and LPS-treated mice, with the antidepressant-like effects sustained for 5 d. Similar to JWX or Scop, GMA rapidly reduced the neuroinflammation signaling of Iba-1-NF-кB, enhanced neuroplasticity signaling of CaMKII-mTOR-BDNF, and attenuated the upregulated expressions of the NMDAR sub-units GluN1 and GluN2B in the hippocampus of LPS-treated mice. GMA, JWX and Scop rapidly restored the number of BDNF-positive cells reduced by LPS treatment in the CA3 region of the hippocampus. Furthermore, rapamycin, a selective inhibitor of mTOR, blunted the rapid antidepressant-like effects and hippocampal BDNF signaling upregulation by GMA. CONCLUSION: GMA may serve as a refined formula from JWX, capable of inducing rapid antidepressant-like effects. In the LPS-induced depression model, the effects of GMA were mediated via rapidly alleviating neuroinflammation and enhancing neuroplasticity.
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Antidepresivos , Depresión , Medicamentos Herbarios Chinos , Lipopolisacáridos , Enfermedades Neuroinflamatorias , Plasticidad Neuronal , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Antidepresivos/farmacología , Plasticidad Neuronal/efectos de los fármacos , Masculino , Depresión/tratamiento farmacológico , Depresión/inducido químicamente , Ratones , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Paeonia/química , Ratones Endogámicos C57BL , Gardenia/química , Modelos Animales de Enfermedad , Serina-Treonina Quinasas TOR/metabolismo , Conducta Animal/efectos de los fármacosRESUMEN
Treatment-resistant depression (TRD) is defined as patients diagnosed with depression having a history of failure with different antidepressants with an adequate dosage and treatment duration. The NMDA receptor antagonist ketamine rapidly reduces depressive symptoms in TRD. We examined neural correlates of treatment response to ketamine in TRD through a systematic review of brain magnetic resonance imaging (MRI) studies. A comprehensive search in PubMed was performed using "ketamine AND depression AND magnetic resonance." The time span for the database queries was "Start date: 2018/01/01; End date: 2024/05/31." Total 41 original articles comprising 1,396 TRD and 587 healthy controls (HC) were included. Diagnosis of depression was made using the Structured Clinical Interview for DSM Disorders (SCID), the Mini-International Neuropsychiatric Interview (MINI), and/or the clinical assessment by psychiatrists. Patients with affective psychotic disorders were excluded. Most studies applied ketamine [0.5mg/kg racemic ketamine and/or 0.25mg/kg S-ketamine] diluted in 60cc of normal saline via intravenous infusion over 40 min one time, four times, or six times spaced 2-3 days apart over 2 weeks. Clinical outcome was defined as either remission, response, and/or percentage changes of depressive symptoms. Brain MRI of the T2*-weighted imaging (resting-state or task performance), arterial spin labeling, diffusion weighted imaging, and T1-weighted imaging were acquired at baseline and mainly 1-3days after the ketamine administration. Only the study results replicated by ≥ 2 studies and were included in the default-mode, salience, fronto-parietal, subcortical, and limbic networks were regarded as meaningful. Putative brain-based markers of treatment response to ketamine in TRD were found in the structural/functional features of limbic (subgenual ACC, hippocampus, cingulum bundle-hippocampal portion; anhedonia/suicidal ideation), salience (dorsal ACC, insula, cingulum bundle-cingulate gyrus portion; thought rumination/suicidal ideation), fronto-parietal (dorsolateral prefrontal cortex, superior longitudinal fasciculus; anhedonia/suicidal ideation), default-mode (posterior cingulate cortex; thought rumination), and subcortical (striatum; anhedonia/thought rumination) networks. Brain features of limbic, salience, and fronto-parietal networks could be useful in predicting the TRD with better response to ketamine in relief of anhedonia, thought rumination, and suicidal ideation.
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Trastorno Depresivo Resistente al Tratamiento , Ketamina , Imagen por Resonancia Magnética , Ketamina/farmacología , Ketamina/administración & dosificación , Humanos , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/diagnóstico por imagen , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Depression impairs not only central nervous system, but also peripheral systems of the host. Gut microbiota have been proved to be involved in the pathogenesis of depression. Xiaoyaosan (XYS) has a history of over a thousand years in China for treating depression, dramatically alleviating anxiety, cognitive disorders, and especially gastrointestinal dysfunctions. Yet, it still just scratches the surface of the anti-depression mechanisms of XYS. AIM OF THE STUDY: This study aims to elucidate the mechanism of actions of XYS from the perspective of "microbiota-gut-brain" axis. MATERIALS AND METHODS: We firstly evaluated the effects of XYS on the macroscopic behaviors of depressed rats that induced by chronic unpredictable mild stress (CUMS). Secondly, the effects of XYS on intestinal homeostasis of depressed rats were revealed by using dysbacteriosis model. Subsequently, the underlying mechanisms were demonstrated by 16S rRNA gene sequencing technology and molecular biology methods. Finally, correlation analysis and visualization of the anti-depression effects of XYS were performed from the "microbiota - gut - brain" perspective. RESULTS: Our data indicated that XYS ameliorated the depression-like symptoms of CUMS rats, partly depending on the presence of gut microbiota. Furthermore, we illustrated that XYS reversed CUMS-induced gut dysbiosis of depressed rats in terms of decreasing the Bacteroidetes/Firmicutes ratio and the abundances of Bacteroides, and Corynebacterium, while increasing the abundances of Lactobacillus and Adlercreutzia. The significant enrichment of Bacteroides and the level of lipopolysaccharides (LPS) suggested that depression damaged the immune responses and gut barrier. Mechanistically, XYS significantly down-regulated the expression levels of factors that involved in TLR4/NLRP3 signaling pathway in the colon and brain tissues of depressed rats. In addition, XYS significantly increased the levels of claudin 1 and ZO-1, showing that XYS positively maintained the integrity of gut and blood-brain barriers (BBB). CONCLUSION: Our study offers insights into the anti-depression effects of XYS through a lens of "microbiota-TLR4/NLRP3 signaling pathway-barriers", providing a foundation for enhancing clinical efficiency and enriching drug selection, and contributing to our understanding of the mechanisms of traditional Chinese medicines (TCMs) in treating depression.
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Antidepresivos , Eje Cerebro-Intestino , Depresión , Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Lipopolisacáridos , Proteína con Dominio Pirina 3 de la Familia NLR , Ratas Sprague-Dawley , Transducción de Señal , Receptor Toll-Like 4 , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Masculino , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratas , Eje Cerebro-Intestino/efectos de los fármacos , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/psicología , Estrés Psicológico/metabolismo , Disbiosis/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de EnfermedadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Depression is a prevalent stress disorder, yet the underlying physiological mechanisms linking stress to appetite and weight loss remain elusive. While most antidepressants are associated with excessive weight and appetite gain, sertraline (SER) exhibits a lower risk of these side effects. Metacinnabar (ß-HgS), the primary component of Tibetan medicine Zuotai, has been shown to enhance mice's resilience against external stress without causing excessive increases in weight or appetite. However, the precise physiological pathway through which ß-HgS restores appetite and weight in stressed mice remains unclear. AIM OF THE STUDY: The objective of this study is to assess the efficacy of ß-HgS in ameliorating weight loss and appetite suppression induced by pressure stimulation in mice, as well as elucidate its potential mechanisms of action. METHODS: The present study employed chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) as experimental models to simulate environmental stress encountered in daily life. Subsequently, a series of experiments were conducted, including behavior tests, HE staining of rectal and hippocampal pathological sections, detection of depression-related biological indicators, analysis of intestinal flora diversity, as well as metabolomics analysis of hippocampal and intestinal contents. RESULT: Dysregulation of glycerophospholipid metabolism may represent the principal pathway underlying reduced appetite, body weight, neurotransmitter and appetite hormone levels, heightened inflammatory response, hippocampal and rectal tissue damage, as well as altered composition of intestinal microbiota in stressed mice. Following intervention with SER and ß-HgS in stressed mice, the deleterious effects induced by stress can be ameliorated, in which the medium-dose ß-HgS exhibited superior performance. CONCLUSION: The aforementioned research findings suggest that the stress-induced decrease in appetite and body weight in mice may be associated with dysregulation in glycerophospholipid metabolism connecting the gut-brain axis. ß-HgS exhibits potential in ameliorating depressive-like symptoms in mice subjected to stress, while concurrently restoring their body weight and appetite without inducing excessive augmentation. Its therapeutic effect may also be attributed to its ability to modulate glycerophospholipid metabolism status and exert influence on the gut-brain axis.
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Apetito , Microbioma Gastrointestinal , Estrés Psicológico , Animales , Masculino , Estrés Psicológico/tratamiento farmacológico , Ratones , Apetito/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Depresión/tratamiento farmacológico , Antidepresivos/farmacología , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Conducta Animal/efectos de los fármacosRESUMEN
BACKGROUND: Schisandra chinensis lignan (SCL), a major active component of the traditional functional Chinese medicine Schisandra chinensis, has been reported to have antidepressant effects. Its mechanisms include alleviating intestinal barrier injury (IBI) by resolving intestinal microflora, anti-inflammation, and neuroprotection. SCL also regulates endogenous cannabinoid system, and it is closely related to the onset and development of depression. PURPOSE: We investigated a new treatment strategy for depression, i.e., alleviating IBI by regulating the endogenous cannabinoid system for antidepressant effects, as well as conducted in-depth research to explore the specific mechanism. METHODS: Behavioral analysis was conducted to detect the occurrence of depressive-like behavior in C57BL/6 mice. We used hematoxylin-eosin staining, periodic acid-Schiff staining, and immunofluorescence to evaluate IBI. Network pharmacology and Western blotting (WB) were used to predict and confirm that the amelioration effect of SCL was associated with anti-inflammation and anti-apoptosis. Combined with the levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG), we conducted the Pearson analysis between the AEA, 2-AG levels and the major targets identified and validated by network pharmacology and WB. Subsequently, URB-597, a fatty acid amide hydrolase (FAAH) antagonist with an AEA hydrolase-inhibiting effect, was administered to the mice, and behavioral analysis and apoptotic proteins were verified. Plasma endocannabinoid levels after URB-597 supplementation were measured via 6470 Triple Quadrupole LC/MS. Finally, the cannabinoid receptor type 2 (CB2R) antagonist AM630 was administered to mice, and immunofluorescence and WB were performed to assess the proteins of IBI and anti-inflammation. RESULTS: The study demonstrated that SCL alleviated depressive-like behaviours and ameliorated IBI. Network pharmacology and WB confirmed that the improvement of IBI was related to the anti-inflammatory and anti-apoptotic pathways. Pearson results showed that AEA levels were positively correlated with inflammation and apoptosis, with a greater contribution to apoptosis. In-depth studies validated that the URB-597 administration reversed the positive effects of SCL on depressive-like behavior and anti-apoptosis. Similarly, URB-597 counteracted AEA levels reduced by SCL and decreased 2-AG levels. Furthermore, AM630 supplementation antagonized SCL's effect of improving IBI by reactivating the MAPK/NF-κB inflammation pathway. CONCLUSION: Overall, SCL, in collaboration with the endogenous cannabinoid system regulated by SCL, alleviates depression associated IBI. The specific mechanism involes SCL decreasing AEA levels to inhibit colon tissue cell apoptosis by up-regulating FAAH. Simultaneously, it directly triggers CB2R to reduce inflammation responses, further alleviating IBI.
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Antidepresivos , Ácidos Araquidónicos , Depresión , Endocannabinoides , Lignanos , Ratones Endogámicos C57BL , Alcamidas Poliinsaturadas , Schisandra , Animales , Lignanos/farmacología , Depresión/tratamiento farmacológico , Masculino , Alcamidas Poliinsaturadas/farmacología , Schisandra/química , Antidepresivos/farmacología , Ratones , Apoptosis/efectos de los fármacos , Glicéridos/farmacología , Farmacología en Red , Amidohidrolasas/metabolismo , Receptor Cannabinoide CB2/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Antiinflamatorios/farmacología , Benzamidas , Carbamatos , IndolesRESUMEN
Neoponcirin causes anxiolytic-like effects in mice when administered intraperitoneally but not orally. Neoponcirin is non-water-soluble and insoluble in solvents, and in medium acid, it isomerizes, reducing its bioavailability. To improve the pharmacological properties of neoponcirin, we formed a neoponcirin complex with beta-cyclodextrin (NEO/ßCD), which was characterized by FT-IR, UV-Vis, and NMR, and their solubility profile. We evaluated the antidepressant-like effects of NEO/ßCD acutely administered to mice orally in the behavioral paradigms, the tail suspension (TST) and the forced swimming (FST) tests. We also analyzed the benefits of repeated oral doses of NEO/ßCD on depression- and anxiety-like behaviors induced in mice by chronic unpredictable mild stress (CUMS), using the FST, hole board, and open field tests. We determined the stressed mice's expression of stress-related inflammatory cytokines (IL-1ß, IL-6, and TNFα) and corticosterone. Results showed that a single or chronic oral administration of NEO/ßCD caused a robust antidepressant-like effect without affecting the ambulatory activity. In mice under CUMS, NEO/ßCD also produced anxiolytic-like effects and avoided increased corticosterone and IL-1ß levels. The effects of the NEO/ßCD complex were robust in both the acute and the stress chronic models, improving brain neurochemistry and recovering immune responses previously affected by prolonged stress.
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Antidepresivos , Depresión , Estrés Psicológico , beta-Ciclodextrinas , Animales , beta-Ciclodextrinas/farmacología , beta-Ciclodextrinas/química , Ratones , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Masculino , Estrés Psicológico/tratamiento farmacológico , Depresión/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Ansiedad/tratamiento farmacológico , Ansiolíticos/farmacología , Natación , Administración OralRESUMEN
Depression is a common mood disorder and many patients do not respond to conventional pharmacotherapy or experience a variety of adverse effects. This work proposed that riparin I (RIP I) and riparin II (RIP II) present neuroprotective effects through modulation of astrocytes and microglia, resulting in the reversal of depressive-like behaviors. To verify our hypothesis and clarify the pathways underlying the effect of RIP I and RIP II on neuroinflammation, we used the chronic unpredictable mild stress (CUMS) depression model in mice. Male Swiss mice were exposed to stressors for 28â days. From 15 th to the 22 nd day, the animals received RIP I or RIP II (50â mg/kg) or fluoxetine (FLU, 10â mg/kg) or vehicle, by gavage. On the 29 th day, behavioral tests were performed. Expressions of microglia (ionized calcium-binding adaptor molecule-1 - Iba-1) and astrocyte (glial fibrillary acidic protein - GFAP) markers and levels of cytokines tumor necrosis factor alfa (TNF-α) and interleukin 1 beta (IL-1ß) were measured in the hippocampus. CUMS induced depressive-like behaviors and cognitive impairment, high TNF-α and IL-1ß levels, decreased GFAP, and increased Iba-1 expressions. RIP I and RIP II reversed these alterations. These results contribute to the understanding the mechanisms underlying the antidepressant effect of RIP I and RIP II, which may be related to neuroinflammatory suppression.
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Antidepresivos , Astrocitos , Depresión , Modelos Animales de Enfermedad , Hipocampo , Microglía , Enfermedades Neuroinflamatorias , Estrés Psicológico , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ratones , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Depresión/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Fluoxetina/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-1beta/metabolismo , Fármacos Neuroprotectores/farmacología , Conducta Animal/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismoRESUMEN
Ketamine has been found to have rapid and potent antidepressant activity. However, despite the ubiquitous brain expression of its molecular target, the N-methyl-d-aspartate receptor (NMDAR), it was not clear whether there is a selective, primary site for ketamine's antidepressant action. We found that ketamine injection in depressive-like mice specifically blocks NMDARs in lateral habenular (LHb) neurons, but not in hippocampal pyramidal neurons. This regional specificity depended on the use-dependent nature of ketamine as a channel blocker, local neural activity, and the extrasynaptic reservoir pool size of NMDARs. Activating hippocampal or inactivating LHb neurons swapped their ketamine sensitivity. Conditional knockout of NMDARs in the LHb occluded ketamine's antidepressant effects and blocked the systemic ketamine-induced elevation of serotonin and brain-derived neurotrophic factor in the hippocampus. This distinction of the primary versus secondary brain target(s) of ketamine should help with the design of more precise and efficient antidepressant treatments.