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1.
Eur J Pharmacol ; 976: 176693, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38834095

RESUMO

ß-arrestin2 is a versatile protein for signaling transduction in brain physiology and pathology. Herein, we investigated the involvement of ß-arrestin2 in pharmacological effects of fluoxetine for depression. A chronic mild stress (CMS) model was established using wild-type (WT) and ß-arrestin2-/- mice. Behavioral results demonstrated that CMS mice showed increased immobility time in the tail suspension test and forced swimming test, elevated concentrations of pro-inflammatory factors in peripheral blood, increased expression of pyroptosis-related proteins, and increased co-labeling of glial fibrillary acidic protein and Caspase1 p10 in the hippocampus compared to the CON group. Treatment with fluoxetine (FLX) ameliorated these conditions. However, compared with the ß-arrestin2-/- CMS group, these results of the ß-arrestin2-/- CMS + FLX group showed no significant changes. These results suggested that the above effects of FLX could be eliminated by knocking out ß-arrestin2. Mass spectrometry implying that FLX promoted the binding of ß-arrestin2 to the NLRP2 inflammasome of depressed mice. Subsequently, the results of the cellular experiments suggested that the 5HT2B receptor antagonist may attenuate L-kynurenine + ATP-induced cell pyroptosis by attenuating NLRP2 binding to ß-arrestin2. We further found that the lack of ß-arrestin2 eliminated the anti-pyroptosis effect of fluoxetine. In conclusion, ß-arrestin2 is an essential protein for fluoxetine to alleviate pyroptosis in the hippocampal astrocytes of CMS mice. Mechanistically, we found that the 5-HT2BR-ß-arrestin2-NLRP2 axis is vital for maintaining the antidepressant effects of fluoxetine.


Assuntos
Antidepressivos , Astrócitos , Depressão , Modelos Animais de Doenças , Fluoxetina , Piroptose , Estresse Psicológico , beta-Arrestina 2 , Animais , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Piroptose/efeitos dos fármacos , beta-Arrestina 2/metabolismo , Camundongos , Depressão/tratamento farmacológico , Depressão/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Masculino , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Camundongos Endogâmicos C57BL , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos Knockout , Comportamento Animal/efeitos dos fármacos , Inflamassomos/metabolismo , Doença Crônica
2.
Sci Rep ; 14(1): 13559, 2024 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-38866877

RESUMO

Naringenin (NAR) has various biological activities but low bioavailability. The current study examines the effect of Naringenin-loaded hybridized nanoparticles (NAR-HNPs) and NAR on depression induced by streptozotocin (STZ) in rats. NAR-HNPs formula with the highest in vitro NAR released profile, lowest polydispersity index value (0.21 ± 0.02), highest entrapment efficiency (98.7 ± 2.01%), as well as an acceptable particle size and zeta potential of 415.2 ± 9.54 nm and 52.8 ± 1.04 mV, respectively, was considered the optimum formulation. It was characterized by differential scanning calorimetry, examined using a transmission electron microscope, and a stability study was conducted at different temperatures to monitor its stability efficiency showing that NAR-HNP formulation maintains stability at 4 °C. The selected formulation was subjected to an acute toxicological test, a pharmacokinetic analysis, and a Diabetes mellitus (DM) experimental model. STZ (50 mg/kg) given as a single i.p. rendered rats diabetic. Diabetic rat groups were allocated into 4 groups: one group received no treatment, while the remaining three received oral doses of unloaded HNPs, NAR (50 mg/kg), NAR-HNPs (50 mg/kg) and NAR (50 mg/kg) + peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist, GW9662 (1mg/kg, i.p.) for three weeks. Additional four non-diabetic rat groups received: distilled water (normal), free NAR, and NAR-HNPs, respectively for three weeks. NAR and NAR-HNPs reduced immobility time in forced swimming test and serum blood glucose while increasing serum insulin level. They also reduced cortical and hippocampal 5-hydroxyindoeacetic acid, 3,4-Dihydroxy-phenylacetic acid, malondialdehyde, NLR family pyrin domain containing-3 (NLRP3) and interleukin-1beta content while raised serotonin, nor-epinephrine, dopamine and glutathione level. PPAR-γ gene expression was elevated too. So, NAR and NAR-HNPs reduced DM-induced depression by influencing brain neurotransmitters and exhibiting anti-oxidant and anti-inflammatory effects through the activation PPAR-γ/ NLRP3 pathway. NAR-HNPs showed the best pharmacokinetic and therapeutic results.


Assuntos
Antidepressivos , Diabetes Mellitus Experimental , Flavanonas , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nanopartículas , PPAR gama , Animais , Flavanonas/farmacologia , Flavanonas/administração & dosagem , Flavanonas/química , PPAR gama/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nanopartículas/química , Ratos , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estreptozocina , Ratos Wistar , Anilidas
3.
Philos Trans R Soc Lond B Biol Sci ; 379(1906): 20230225, 2024 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-38853549

RESUMO

Substantial clinical evidence has unravelled the superior antidepressant efficacy of ketamine: in comparison to traditional antidepressants targeting the monoamine systems, ketamine, as an N-methyl-d-aspartate receptor (NMDAR) antagonist, acts much faster and more potently. Surrounding the antidepressant mechanisms of ketamine, there is ample evidence supporting an NMDAR-antagonism-based hypothesis. However, alternative arguments also exist, mostly derived from the controversial clinical results of other NMDAR inhibitors. In this article, we first summarize the historical development of the NMDAR-centred hypothesis of rapid antidepressants. We then classify different NMDAR inhibitors based on their mechanisms of inhibition and evaluate preclinical as well as clinical evidence of their antidepressant effects. Finally, we critically analyse controversies and arguments surrounding ketamine's NMDAR-dependent and NMDAR-independent antidepressant action. A better understanding of ketamine's molecular targets and antidepressant mechanisms should shed light on the future development of better treatment for depression. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.


Assuntos
Antidepressivos , Ketamina , Receptores de N-Metil-D-Aspartato , Ketamina/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Humanos , Animais , Depressão/tratamento farmacológico
4.
Nat Commun ; 15(1): 4945, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858386

RESUMO

Single administration of low-dose ketamine has both acute and sustained anti-depressant effects. Sustained effect is associated with restoration of glutamatergic synapses in medial prefrontal cortic (mFPC) neurons. Ketamine induced profound changes in a number of molecular pathways in a mouse model for chronic stress. Cell-cell communication analyses predicted that planar-cell-polarity (PCP) signaling was decreased after chronic administration of corticosterone but increased following ketamine administration in most of the excitatory neurons. Similar decrease of PCP signaling in excitatory neurons was predicted in dorsolateral prefrontal cortical (dl-PFC) neurons of patients with major depressive disorder (MDD). We showed that the basolateral amygdala (BLA)-projecting infralimbic prefrontal cortex (IL PFC) neurons regulate immobility time in the tail suspension test and food consumption. Conditionally knocking out Celsr2 and Celsr3 or Prickle2 in the BLA-projecting IL PFC neurons abolished ketamine-induced synapse restoration and behavioral remission. Therefore, PCP proteins in IL PFC-BLA neurons mediate synapse restoration induced by of low-dose ketamine.


Assuntos
Modelos Animais de Doenças , Ketamina , Neurônios , Córtex Pré-Frontal , Sinapses , Animais , Ketamina/farmacologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Camundongos , Masculino , Humanos , Polaridade Celular/efeitos dos fármacos , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Camundongos Knockout , Estresse Psicológico , Corticosterona , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Proteínas com Domínio LIM/metabolismo , Proteínas com Domínio LIM/genética , Ácido Glutâmico/metabolismo , Antidepressivos/farmacologia
5.
Transl Psychiatry ; 14(1): 238, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834540

RESUMO

The glutamatergic modulator ketamine is associated with changes in sleep, depression, and suicidal ideation (SI). This study sought to evaluate differences in arousal-related sleep metrics between 36 individuals with treatment-resistant major depression (TRD) and 25 healthy volunteers (HVs). It also sought to determine whether ketamine normalizes arousal in individuals with TRD and whether ketamine's effects on arousal mediate its antidepressant and anti-SI effects. This was a secondary analysis of a biomarker-focused, randomized, double-blind, crossover trial of ketamine (0.5 mg/kg) compared to saline placebo. Polysomnography (PSG) studies were conducted one day before and one day after ketamine/placebo infusions. Sleep arousal was measured using spectral power functions over time including alpha (quiet wakefulness), beta (alert wakefulness), and delta (deep sleep) power, as well as macroarchitecture variables, including wakefulness after sleep onset (WASO), total sleep time (TST), rapid eye movement (REM) latency, and Post-Sleep Onset Sleep Efficiency (PSOSE). At baseline, diagnostic differences in sleep macroarchitecture included lower TST (p = 0.006) and shorter REM latency (p = 0.04) in the TRD versus HV group. Ketamine's temporal dynamic effects (relative to placebo) in TRD included increased delta power earlier in the night and increased alpha and delta power later in the night. However, there were no significant diagnostic differences in temporal patterns of alpha, beta, or delta power, no ketamine effects on sleep macroarchitecture arousal metrics, and no mediation effects of sleep variables on ketamine's antidepressant or anti-SI effects. These results highlight the role of sleep-related variables as part of the systemic neurobiological changes initiated after ketamine administration. Clinical Trials Identifier: NCT00088699.


Assuntos
Nível de Alerta , Estudos Cross-Over , Transtorno Depressivo Resistente a Tratamento , Ketamina , Polissonografia , Humanos , Ketamina/administração & dosagem , Ketamina/farmacologia , Masculino , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/fisiopatologia , Feminino , Adulto , Método Duplo-Cego , Nível de Alerta/efeitos dos fármacos , Pessoa de Meia-Idade , Sono/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Vigília/efeitos dos fármacos , Ideação Suicida , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Adulto Jovem
6.
PeerJ ; 12: e17517, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38846751

RESUMO

Background: Psilocybin and related tryptamines have come into the spotlight in recent years as potential therapeutics for depression. Research on the mechanisms of these effects has historically focused on the direct effects of these drugs on neural processes. However, in addition to such neural effects, alterations in peripheral physiology may also contribute to their therapeutic effects. In particular, substantial support exists for a gut microbiome-mediated pathway for the antidepressant efficacy of other drug classes, but no prior studies have determined the effects of tryptamines on microbiota. Methods: To address this gap, in this preliminary study, male Long Evans rats were treated with varying dosages of oral psilocybin (0.2 or 2 mg/kg), norbaeocystin (0.25 or 2.52 mg/kg), or vehicle and their fecal samples were collected 1 week and 3 weeks after exposure for microbiome analysis using integrated 16S ribosomal DNA sequencing to determine gut microbiome composition. Results: We found that although treatment with neither psilocybin nor norbaeocystin significantly affected overall microbiome diversity, it did cause significant dose- and time-dependent changes in bacterial abundance at the phylum level, including increases in Verrucomicrobia and Actinobacteria, and decreases in Proteobacteria. Conclusion and Implications: These preliminary findings support the idea that psilocybin and other tryptamines may act on the gut microbiome in a dose- and time-dependent manner, potentially identifying a novel peripheral mechanism for their antidepressant activity. The results from this preliminary study also suggest that norbaeocystin may warrant further investigation as a potential antidepressant, given the similarity of its effects to psilocybin.


Assuntos
Fezes , Microbioma Gastrointestinal , Ratos Long-Evans , Triptaminas , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Triptaminas/farmacologia , Triptaminas/administração & dosagem , Ratos , Fezes/microbiologia , Psilocibina/farmacologia , Psilocibina/administração & dosagem , Administração Oral , Antidepressivos/farmacologia , Antidepressivos/administração & dosagem
7.
Top Curr Chem (Cham) ; 382(2): 20, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38829467

RESUMO

Cannabis sativa has long been used for neurological and psychological healing. Recently, cannabidiol (CBD) extracted from cannabis sativa has gained prominence in the medical field due to its non-psychotropic therapeutic effects on the central and peripheral nervous systems. CBD, also acting as a potent antioxidant, displays diverse clinical properties such as anticancer, antiinflammatory, antidepressant, antioxidant, antiemetic, anxiolytic, antiepileptic, and antipsychotic effects. In this review, we summarized the structural activity relationship of CBD with different receptors by both experimental and computational techniques and investigated the mechanism of interaction between related receptors and CBD. The discovery of structural activity relationship between CBD and target receptors would provide a direction to optimize the scaffold of CBD and its derivatives, which would give potential medical applications on CBD-based therapies in various illnesses.


Assuntos
Canabidiol , Canabidiol/química , Canabidiol/farmacologia , Canabidiol/metabolismo , Humanos , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Cannabis/química , Relação Estrutura-Atividade , Receptores de Canabinoides/metabolismo , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antidepressivos/química , Antidepressivos/farmacologia
8.
Nat Commun ; 15(1): 5042, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38871707

RESUMO

Mood disorders are an enigmatic class of debilitating illnesses that affect millions of individuals worldwide. While chronic stress clearly increases incidence levels of mood disorders, including major depressive disorder (MDD), stress-mediated disruptions in brain function that precipitate these illnesses remain largely elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding direct roles for serotonin in the precipitation and treatment of affective disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this non-canonical phenomenon has not yet been explored following stress and/or AD exposures. Here, we employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress, as well as in DRN of human MDD patients, to examine the impact of stress exposures/MDD diagnosis on H3K4me3Q5ser dynamics, as well as associations between the mark and depression-related gene expression. We additionally assessed stress-induced/MDD-associated regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy in mice to reduce H3K4me3Q5ser levels in DRN and examine its impact on stress-associated gene expression and behavior. We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to attenuate stress-mediated gene expression and behavior. Corresponding patterns of H3K4me3Q5ser regulation were observed in MDD subjects on vs. off ADs at their time of death. These findings thus establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity, observations of which may be of clinical relevance to human MDD and its treatment.


Assuntos
Antidepressivos , Transtorno Depressivo Maior , Núcleo Dorsal da Rafe , Histonas , Estresse Psicológico , Animais , Núcleo Dorsal da Rafe/metabolismo , Núcleo Dorsal da Rafe/efeitos dos fármacos , Histonas/metabolismo , Masculino , Feminino , Estresse Psicológico/metabolismo , Humanos , Antidepressivos/farmacologia , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/tratamento farmacológico , Camundongos , Serotonina/metabolismo , Camundongos Endogâmicos C57BL , Epigênese Genética/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Derrota Social
9.
Int J Mol Sci ; 25(11)2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38892026

RESUMO

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.


Assuntos
Antidepressivos , Depressão , Frutas , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Extratos Vegetais , Rosaceae , Animais , Antidepressivos/farmacologia , Antidepressivos/química , Masculino , Camundongos , Frutas/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Depressão/tratamento farmacológico , Rosaceae/química , Comportamento Animal/efeitos dos fármacos , Monoaminoxidase/metabolismo , Modelos Animais de Doenças , Corticosterona , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/química , Ácido Clorogênico/farmacologia , Ácido Clorogênico/química , População do Leste Asiático
10.
Molecules ; 29(11)2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38893335

RESUMO

Depression is a chronic, severe, and often life-threatening neurological disorder. It not only causes depression in patients and affects daily life but, in severe cases, may lead to suicidal behavior and have adverse effects on families and society. In recent years, it has been found that sub-anesthetic doses of ketamine have a rapid antidepressant effect on patients with treatment-resistant depression and can significantly reduce the suicidal tendencies of patients with major depressive disorder. Current studies suggest that ketamine may exert antidepressant effects by blocking NMDAR ion channels, but its anesthetic and psychotomimetic side effects limit its application. Here, we report efforts to design and synthesize a novel series of ketamine derivatives of NMDAR antagonists, among which compounds 23 and 24 have improved activity compared with ketamine, introducing a new direction for the development of rapid-acting antidepressant drugs.


Assuntos
Antidepressivos , Desenho de Fármacos , Ketamina , Receptores de N-Metil-D-Aspartato , Ketamina/química , Ketamina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Antidepressivos/farmacologia , Antidepressivos/síntese química , Antidepressivos/química , Humanos , Animais , Relação Estrutura-Atividade , Camundongos
11.
Medicine (Baltimore) ; 103(24): e38496, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38875413

RESUMO

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.


Assuntos
Antidepressivos , Receptor 5-HT1A de Serotonina , Agonistas do Receptor 5-HT1 de Serotonina , Humanos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Piperazinas/farmacologia , Piperazinas/química , Benzotiazóis/farmacologia , Benzotiazóis/química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Piperidinas/química , Pirrolidinonas/farmacologia , Pirrolidinonas/uso terapêutico , Pirrolidinonas/química , Depressão/tratamento farmacológico
12.
Brain Behav ; 14(6): e3511, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38894648

RESUMO

INTRODUCTION: Major depressive disorder (MDD) is associated with dysfunctional reward processing, which involves functional circuitry of the habenula (Hb) and nucleus accumbens (NAc). Since ketamine elicits rapid antidepressant and antianhedonic effects in MDD, this study sought to investigate how serial ketamine infusion (SKI) treatment modulates static and dynamic functional connectivity (FC) in Hb and NAc functional networks. METHODS: MDD participants (n = 58, mean age = 40.7 years, female = 28) received four ketamine infusions (0.5 mg/kg) 2-3 times weekly. Resting-state functional magnetic resonance imaging (fMRI) scans and clinical assessments were collected at baseline and 24 h post-SKI. Static FC (sFC) and dynamic FC variability (dFCv) were calculated from left and right Hb and NAc seeds to all other brain regions. Changes in FC pre-to-post SKI, and correlations with changes with mood and anhedonia were examined. Comparisons of FC between patients and healthy controls (HC) at baseline (n = 55, mean age = 32.6, female = 31), and between HC assessed twice (n = 16) were conducted as follow-up analyses. RESULTS: Following SKI, significant increases in left Hb-bilateral visual cortex FC, decreases in left Hb-left inferior parietal cortex FC, and decreases in left NAc-right cerebellum FC occurred. Decreased dFCv between left Hb and right precuneus and visual cortex, and decreased dFCv between right NAc and right visual cortex both significantly correlated with improvements in mood ratings. Decreased FC between left Hb and bilateral visual/parietal cortices as well as increased FC between left NAc and right visual/parietal cortices both significantly correlated with improvements in anhedonia. No differences were observed between HC at baseline or over time. CONCLUSION: Subanesthetic ketamine modulates functional pathways linking the Hb and NAc with visual, parietal, and cerebellar regions in MDD. Overlapping effects between Hb and NAc functional systems were associated with ketamine's therapeutic response.


Assuntos
Transtorno Depressivo Maior , Habenula , Ketamina , Imageamento por Ressonância Magnética , Núcleo Accumbens , Humanos , Ketamina/farmacologia , Ketamina/administração & dosagem , Masculino , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/diagnóstico por imagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/diagnóstico por imagem , Núcleo Accumbens/fisiopatologia , Adulto , Feminino , Habenula/efeitos dos fármacos , Habenula/fisiopatologia , Habenula/diagnóstico por imagem , Pessoa de Meia-Idade , Antidepressivos/farmacologia , Antidepressivos/administração & dosagem , Anedonia/efeitos dos fármacos , Anedonia/fisiologia
13.
Transl Psychiatry ; 14(1): 258, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890270

RESUMO

Neuroimaging studies have identified the anterior cingulate cortex (ACC) as one of the major targets of ketamine in the human brain, which may be related to ketamine's antidepressant (AD) mechanisms of action. However, due to different methodological approaches, different investigated populations, and varying measurement timepoints, results are not consistent, and the functional significance of the observed brain changes remains a matter of open debate. Inhibition of glutamate release during acute ketamine administration by lamotrigine provides the opportunity to gain additional insight into the functional significance of ketamine-induced brain changes. Furthermore, the assessment of trait negative emotionality holds promise to link findings in healthy participants to potential AD mechanisms of ketamine. In this double-blind, placebo-controlled, randomized, single dose, parallel-group study, we collected resting-state fMRI data before, during, and 24 h after ketamine administration in a sample of 75 healthy male and female participants who were randomly allocated to one of three treatment conditions (ketamine, ketamine with lamotrigine pre- treatment, placebo). Spontaneous brain activity was extracted from two ventral and one dorsal subregions of the ACC. Our results showed activity decreases during the administration of ketamine in all three ACC subregions. However, only in the ventral subregions of the ACC this effect was attenuated by lamotrigine. 24 h after administration, ACC activity returned to baseline levels, but group differences were observed between the lamotrigine and the ketamine group. Trait negative emotionality was closely linked to activity changes in the subgenual ACC after ketamine administration. These results contribute to an understanding of the functional significance of ketamine effects in different subregions of the ACC by combining an approach to modulate glutamate release with the assessment of multiple timepoints and associations with trait negative emotionality in healthy participants.


Assuntos
Emoções , Giro do Cíngulo , Ketamina , Lamotrigina , Imageamento por Ressonância Magnética , Humanos , Ketamina/farmacologia , Ketamina/administração & dosagem , Lamotrigina/farmacologia , Lamotrigina/administração & dosagem , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/metabolismo , Masculino , Feminino , Método Duplo-Cego , Adulto , Emoções/efeitos dos fármacos , Adulto Jovem , Antidepressivos/farmacologia , Antidepressivos/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem
14.
Int J Neuropsychopharmacol ; 27(6)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38833581

RESUMO

BACKGROUND: The NMDA antagonist S-ketamine is gaining increasing use as a rapid-acting antidepressant, although its exact mechanisms of action are still unknown. In this study, we investigated ketamine in respect to its properties toward central noradrenergic mechanisms and how they influence alertness behavior. METHODS: We investigated the influence of S-ketamine on the locus coeruleus (LC) brain network in a placebo-controlled, cross-over, 7T functional, pharmacological MRI study in 35 healthy male participants (25.1 ± 4.2 years) in conjunction with the attention network task to measure LC-related alertness behavioral changes. RESULTS: We could show that acute disruption of the LC alertness network to the thalamus by ketamine is related to a behavioral alertness reduction. CONCLUSION: The results shed new light on the neural correlates of ketamine beyond the glutamatergic system and underpin a new concept of how it may unfold its antidepressant effects.


Assuntos
Atenção , Estudos Cross-Over , Ketamina , Locus Cerúleo , Imageamento por Ressonância Magnética , Humanos , Ketamina/farmacologia , Ketamina/administração & dosagem , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/diagnóstico por imagem , Locus Cerúleo/fisiologia , Masculino , Adulto , Adulto Jovem , Atenção/efeitos dos fármacos , Atenção/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Método Duplo-Cego , Antidepressivos/farmacologia , Antidepressivos/administração & dosagem
15.
Int Immunopharmacol ; 136: 112330, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-38823180

RESUMO

An inflammatory response is one of the pathogeneses of depression. The anti-inflammatory and neuroprotective effects of auraptene have previously been confirmed. We established an inflammatory depression model by lipopolysaccharide (LPS) injection combined with unpredictable chronic mild stress (uCMS), aiming to explore the effects of auraptene on depressive-like behaviors in adult mice. Mice were divided into a control group, vehicle group, fluoxetine group, celecoxib group, and auraptene group. Then, behavioral tests were conducted to evaluate the effectiveness of auraptene in ameliorating depressive-like behavior. Cyclooxygenase-2 (COX-2), C-reactive protein (CRP), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) were examined by ELISA. Interleukin-10 (IL-10), interleukin-4 (IL-4), and transforming growth factor-ß (TGF-ß) were examined by protein chip technology. The morphology of microglia was observed by the immunohistochemical method. The data showed that, compared with the control group, the vehicle group mice exhibited a depressive-like behavioral phenotype, accompanied by an imbalance in inflammatory cytokines and the activation of microglia in the hippocampus. The depressive behaviors of the auraptene group's mice were significantly alleviated, along with the decrease in pro-inflammatory factors and increase in anti-inflammatory factors, while the activation of microglia was inhibited in the hippocampus. Subsequently, we investigated the role of auraptene in vitro-cultured BV-2 cells treated with LPS. The analysis showed that auraptene downregulated the expression of IL-6, TNF-α, and NO, and diminished the ratio of CD86/CD206. The results showed that auraptene reduced the excessive phagocytosis and ROS production of LPS-induced BV2 cells. In conclusion, auraptene relieved depressive-like behaviors in mice probably via modulating hippocampal neuroinflammation mediated by microglia.


Assuntos
Cumarínicos , Citocinas , Depressão , Hipocampo , Lipopolissacarídeos , Microglia , Estresse Psicológico , Animais , Microglia/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Depressão/tratamento farmacológico , Depressão/imunologia , Depressão/induzido quimicamente , Camundongos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/imunologia , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Citocinas/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Modelos Animais de Doenças , Comportamento Animal/efeitos dos fármacos , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/imunologia , Camundongos Endogâmicos C57BL , Mediadores da Inflamação/metabolismo
16.
Acta Biochim Pol ; 71: 12569, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38812493

RESUMO

Depression is a common psychiatric disorder. Due to the disadvantages of current clinical drugs, including poor efficacy and unnecessary side effects, research has shifted to novel natural products with minimal or no adverse effects as therapeutic alternatives. The ocean is a vast ecological home, with a wide variety of organisms that can produce a large number of natural products with unique structures, some of which have neuroprotective effects and are a valuable source for the development of new drugs for depression. In this review, we analyzed preclinical and clinical studies of natural products derived from marine organisms with antidepressant potential, including the effects on the pathophysiology of depression, and the underlying mechanisms of these effects. It is expected to provide a reference for the development of new antidepressant drugs.


Assuntos
Antidepressivos , Organismos Aquáticos , Produtos Biológicos , Depressão , Produtos Biológicos/uso terapêutico , Produtos Biológicos/farmacologia , Humanos , Antidepressivos/uso terapêutico , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Animais
17.
Artigo em Inglês | MEDLINE | ID: mdl-38762160

RESUMO

Cannabidiol (CBD) is a phytocannabinoid devoid of psychostimulant properties and is currently under investigation as a potential antidepressant drug. However, the mechanisms underlying CBD's antidepressant effects are not yet well understood. CBD targets include a variety of receptors, enzymes, and transporters, with different binding-affinities. Neurochemical and pharmacological evidence indicates that both serotonin and BDNF-TrkB signalling in the prefrontal cortex are necessary for the antidepressant effects induced by CBD in animal models. Herein, we reviewed the current literature to dissect if these are independent mechanisms or if CBD-induced modulation of the serotonergic neurotransmission could mediate its neuroplastic effects through subsequent regulation of BDNF-TrkB signalling, thus culminating in rapid neuroplastic changes. It is hypothesized that: a) CBD interaction with serotonin receptors on neurons of the dorsal raphe nuclei and the resulting disinhibition of serotonergic neurons would promote rapid serotonin release in the PFC and hence its neuroplastic and antidepressant effects; b) CBD facilitates BDNF-TRKB signalling, especially in the PFC, which rapidly triggers neurochemical and neuroplastic effects. These hypotheses are discussed with perspectives for new drug development and clinical applications.


Assuntos
Antidepressivos , Fator Neurotrófico Derivado do Encéfalo , Canabidiol , Receptor trkB , Serotonina , Transdução de Sinais , Canabidiol/farmacologia , Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Serotonina/metabolismo , Animais , Humanos , Transdução de Sinais/efeitos dos fármacos , Receptor trkB/metabolismo
18.
Neurosci Lett ; 833: 137828, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38772437

RESUMO

There is a critical need for safer and better-tolerated alternatives to address the current limitations of antidepressant treatments for major depressive disorder. Recently, drugs targeting the GABA system via α5-containing GABAA receptors (α5-GABAAR) as negative allosteric modulators (α5-NAMs) have shown promise in alleviating stress-related behaviors in preclinical studies, suggesting that α5-NAMs may have translational relevance as novel antidepressant medications. Here, we evaluated the efficacy of Basmisanil, an α5-NAM that has been evaluated in Phase 2 clinical studies as a cognitive enhancer, in a battery of behavioral tests relevant to coping strategies, motivation, and aversion in male mice, along with plasma and brain pharmacokinetic measurements. Our findings reveal that Basmisanil induces dose-dependent rapid antidepressant-like responses in the forced swim test and sucrose splash test without promoting locomotor stimulating effects. Furthermore, Basmisanil elicits sustained behavioral responses in the female urine sniffing test and sucrose splash test, observed 24 h and 48 h post-treatment, respectively. Bioanalysis of plasma and brain samples confirms effective blood-brain barrier penetration by Basmisanil and extrapolation to previously published data suggest that effects were observed at doses (10 and 30 mg/kg i.p.) corresponding to relatively modest levels of α5-GABAAR occupancy (40-65 %). These results suggest that Basmisanil exhibits a combination of rapid and sustained antidepressant-like effects highlighting the potential of α5-NAMs as a novel therapeutic strategy for depression.


Assuntos
Antidepressivos , Receptores de GABA-A , Animais , Masculino , Receptores de GABA-A/metabolismo , Receptores de GABA-A/efeitos dos fármacos , Antidepressivos/farmacologia , Antidepressivos/farmacocinética , Camundongos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Feminino , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Camundongos Endogâmicos C57BL
19.
J Psychiatr Pract ; 30(3): 181-191, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38819242

RESUMO

Alzheimer disease (AD) is a devastating neurodegenerative disorder that affects millions of individuals worldwide, with no effective cure. The main symptoms include learning and memory loss, and the inability to carry out the simplest tasks, significantly affecting patients' quality of life. Over the past few years, tremendous progress has been made in research demonstrating a link between AD and major depressive disorder (MDD). Evidence suggests that MDD is commonly associated with AD and that it can serve as a precipitating factor for this disease. Antidepressants such as selective serotonin reuptake inhibitors, which are the first line of treatment for MDD, have shown great promise in the treatment of depression in AD, although their effectiveness remains controversial. The goal of this review is to summarize current knowledge regarding the association between AD, MDD, and antidepressant treatment. It first provides an overview of the interaction between AD and MDD at the level of genes, brain regions, neurotransmitter systems, and neuroinflammatory markers. The review then presents current evidence regarding the effectiveness of various antidepressants for AD-related pathophysiology and then finally discusses current limitations, challenges, and future directions.


Assuntos
Doença de Alzheimer , Antidepressivos , Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico
20.
Transl Psychiatry ; 14(1): 200, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714646

RESUMO

Lithium is an effective augmenting agent for depressed patients with inadequate response to standard antidepressant therapy, but numerous adverse effects limit its use. We previously reported that a lithium-mimetic agent, ebselen, promoted a positive emotional bias-an indicator of potential antidepressant activity in healthy participants. We therefore aimed to investigate the effects of short-term ebselen treatment on emotional processing and brain neurochemistry in depressed patients with inadequate response to standard antidepressants. We conducted a double-blind, placebo-controlled 7-day experimental medicine study in 51 patients with major depressive disorder who were currently taking antidepressants but had an inadequate response to treatment. Participants received either ebselen 600 mg twice daily for seven days or identical matching placebo. An emotional testing battery, magnetic resonance spectroscopy and depression and anxiety rating scales were conducted at baseline and after seven days of treatment. Ebselen did not increase the recognition of positive facial expressions in the depressed patient group. However, ebselen increased the response bias towards fear emotion in the signal detection measurement. In the anterior cingulate cortex, ebselen significantly reduced the concentrations of inositol and Glx (glutamate+glutamine). We found no significant differences in depression and anxiety rating scales between visits. Our study did not find any positive shift in emotional bias in depressed patients with an inadequate response to antidepressant medication. We confirmed the ability of ebselen to lower inositol and Glx in the anterior cingulate cortex. These latter effects are probably mediated through inhibition of inositol monophosphatase and glutaminase respectively.


Assuntos
Antidepressivos , Azóis , Transtorno Depressivo Maior , Emoções , Isoindóis , Compostos Organosselênicos , Humanos , Feminino , Masculino , Compostos Organosselênicos/farmacologia , Método Duplo-Cego , Adulto , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Antidepressivos/uso terapêutico , Antidepressivos/farmacologia , Pessoa de Meia-Idade , Emoções/efeitos dos fármacos , Azóis/farmacologia , Espectroscopia de Ressonância Magnética , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/metabolismo , Giro do Cíngulo/metabolismo , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem
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