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BACKGROUND: Appropriately defining and using the minimal important change (MIC) and the minimal clinically important difference (MCID) are crucial for determining whether the results are clinically significant. The aim of this study is to survey the status of randomized controlled trials (RCTs) for insomnia interventions to assess the inclusion and interpretation of MIC/MCID values. METHODS: We conducted a cross-sectional study to survey the status of RCTs for insomnia interventions to assess the inclusion and appropriate interpretation of MIC/MCID values. A literature search was conducted by searching the main sleep medicine journals indexed in PubMed, the Excerpta Medica Database (EMBASE), and the Cochrane Central Register of Controlled Trials (CENTRAL) to identify a broad range of search terms. We included RCTs with no restriction on the intervention. The included studies used the Insomnia Severity Index (ISI) or the Pittsburgh Sleep Quality Index (PSQI) questionnaire as the outcome measures. RESULTS: 81 eligible studies were identified, and more than one-third of the included studies used MIC/MCID (n = 31, 38.3%). Among them, 21 studies with ISI as the outcome used MIC defined as a relative decrease ranging from 3 to 8 points. The most frequently used MIC value was a 6-point decrease (n = 7), followed by 8-point (n = 6) and 7-point decrease (n = 4), a 4 to 5-points decrease (n = 3), and a 30% reduction from baseline; 6 studies used MCID values, ranging from 2.8 to 4 points. The most frequently used MCID value was a 4-point decrease in the ISI (n = 4). 4 studies with PSQI as the outcome used a 3-point change as the MIC (n = 2) and a 2.5 to 2.7-point difference as MCID (n = 2). 4 non-inferiority design studies considered interval estimation when drawing clinically significant conclusions in their MCID usage. CONCLUSIONS: The lack of consistent MIC/MCID interpretation and usage in outcome measures for insomnia highlights the urgent need for further efforts to address this issue and improve reporting practices.
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Relevância Clínica , Ensaios Clínicos Controlados Aleatórios como Assunto , Distúrbios do Início e da Manutenção do Sono , Humanos , Estudos Transversais , Diferença Mínima Clinicamente Importante , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Obsessive-compulsive disorder (OCD) is a chronic, severe psychiatric disorder that has been ranked by the World Health Organization as one of the leading causes of illness-related disability, and first-line interventions are limited in efficacy and have side-effect issues. However, the exact pathophysiology underlying this complex, heterogeneous disorder remains unknown. This scenario is now rapidly changing due to the advancement of powerful technologies that can be used to verify the function of the specific gene and dissect the neural circuits underlying the neurobiology of OCD in rodents. Genetic and circuit-specific manipulation in rodents has provided important insights into the neurobiology of OCD by identifying the molecular, cellular, and circuit events that induce OCD-like behaviors. This review will highlight recent progress specifically toward classic genetic animal models and advanced neural circuit findings, which provide theoretical evidence for targeted intervention on specific molecular, cellular, and neural circuit events.
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Emerging evidence suggests that the gut microbiota is closely related to psychiatric disorders. However, little is known about the role of the gut microbiota in the development of obsessive-compulsive disorder (OCD). Here, to investigate the contribution of gut microbiota to the pathogenesis of OCD, we transplanted fecal microbiota from first-episode, drug-naive OCD patients or demographically matched healthy individuals into antibiotic-treated specific pathogen-free (SPF) mice and showed that colonization with OCD microbiota is sufficient to induce core behavioral deficits, including abnormal anxiety-like and compulsive-like behaviors. The fecal microbiota was analyzed using 16 S rRNA full-length sequencing, and the results demonstrated a clear separation of the fecal microbiota of mice colonized with OCD and control microbiota. Notably, microbiota from OCD-colonized mice resulted in injured neuronal morphology and function in the mPFC, with inflammation in the mPFC and colon. Unbiased metabolomic analyses of the serum and mPFC region revealed the accumulation of succinic acid (SA) in OCD-colonized mice. SA impeded neuronal activity and induced an inflammatory response in both the colon and mPFC, impacting intestinal permeability and brain function, which act as vital signal mediators in gut microbiota-brain-immune crosstalk. Manipulations of dimethyl malonate (DM) have been reported to exert neuroprotective effects by suppressing the oxidation of accumulated succinic acid, attenuating the downstream inflammatory response and neuronal damage, and can help to partly improve abnormal behavior and reduce neuroinflammation and intestinal inflammation in OCD-colonized mice. We propose that the gut microbiota likely regulates brain function and behaviors in mice via succinic acid signaling, which contributes to the pathophysiology of OCD through gut-brain crosstalk and may provide new insights into the treatment of this disorder.
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Oxytocin (OXT), produced and secreted in the paraventricular nucleus and supraoptic nucleus of magnocellular and parvocellular neurons. The diverse presence and activity of oxytocin suggests a potential for this neuropeptide in the pathogenesis and treatment of stress-related neuropsychiatric disorders (anxiety, depression and post-traumatic stress disorder (PTSD)). For a more comprehensive understanding of the mechanism of OXT's anti-stress action, the signaling cascade of OXT binding to targeting stress were summarized. Then the advance of OXT treatment in depression, anxiety, PTSD and the major projection region of OXT neuron were discussed. Further, the efficacy of endogenous and exogenous OXT in stress responses were highlighted in this review. To augment the level of OXT in stress-related neuropsychiatric disorders, current biological strategies were summarized to shed a light on the treatment of stress-induced psychiatric disorders. We also conclude some of the major puzzles in the therapeutic uses of OXT in stress-related neuropsychiatric disorders. Although some questions remain to be resolved, OXT has an enormous potential therapeutic use as a hormone that regulates stress responses.
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Previous studies have speculated that brain activity directly controls immune responses in lymphoid organs. However, the upstream brain regions that control lymphoid organs and how they interface with lymphoid organs to produce stress-induced anxiety-like behavior remain elusive. Using stressed human participants and rat models, we show that CCL5 levels are increased in stressed individuals compared to controls. Stress-inducible CCL5 is mainly produced from cervical lymph nodes (CLN). Retrograde tracing from CLN identifies glutamatergic neurons in the red nucleus (RN), the activities of which are tightly correlated with CCL5 levels and anxiety-like behavior in male rats. Ablation or chemogenetic inhibition of RN glutamatergic neurons increases anxiety levels and CCL5 expression in the serum and CLNs, whereas pharmacogenetic activation of these neurons reduces anxiety levels and CCL5 synthesis after restraint stress exposure. Chemogenetic inhibition of the projection from primary motor cortex to RN elicits anxiety-like behavior and CCL5 synthesis. This brain-lymph node axis provides insights into lymph node tissue as a stress-responsive endocrine organ.
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Núcleo Rubro , Estresse Psicológico , Ratos , Humanos , Masculino , Animais , Estresse Psicológico/metabolismo , Ansiedade/metabolismo , Linfonodos/metabolismo , Encéfalo/metabolismo , Quimiocina CCL5/metabolismoRESUMO
As the organ with the largest contact area with the outside world, the intestine is home to a large number of microorganisms and carries out the main functions of food digestion, absorption, and metabolism. Therefore, there is a very active metabolism of substances and energy in the gut, which is easily attacked by oxygen free radicals. What is more, oxidative stress can gradually and slowly cause very serious damage to the gut. Hence, maintaining redox balance is essential for maintaining environmental balance in the gut. Our previous studies have demonstrated that the extract of Sonchus brachyotus DC. (SBE) has been shown to be capable of repairing oxidative damage, while it has not been demonstrated that it can prevent oxidative stress or how it develops. In this work, we investigated the prevention of oxidative stress and its mechanism in SBE based on the H2O2-induced oxidative damage model in Caco-2 cells; the results indicate that SBE can reduce the contents of ROS and MDA and increase the activities of SOD and CAT in preventing oxidative stress. Then, at the mRNA and protein level, SBE can up-regulate and down-regulate the expression of related genes (NFE2L2, KEAP1, HMOX1, NQO1, SOD1, CAT, and GPX1) and proteins involved in the Nrf2-Keap1-ARE signaling pathway. In conclusion, SBE plays a preventive role in oxidative stress through the Nrf2-Keap1-ARE signaling pathway.
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Those with a negative experience of psychosocial stress during the early stage of life not only have a high susceptibility of the psychiatric disorder in all phases of their life span, but they also demonstrate more severe symptoms and poorer response to treatment compared to those without a history of early-life stress. The interventions targeted to early-life stress may improve the effectiveness of treating and preventing psychiatric disorders. Brain regions associated with mood and cognition develop rapidly and own heightened plasticity during adolescence. So, manipulating nonpharmacological interventions in fewer side effects and higher acceptance during adolescence, which is a probable window of opportunity, may ameliorate or even reverse the constantly deteriorating impact of early-life stress. The present article reviews animal and people studies about adolescent nonpharmacological interventions for early-life stress. We aim to discuss whether those adolescent nonpharmacological interventions can promote individuals' psychological health who expose to early-life stress.
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Experiências Adversas da Infância , Transtornos Mentais , Animais , Transtornos Mentais/terapia , Saúde Mental , Humanos , AdolescenteRESUMO
OBJECTIVES: Neuroinflammation has been suggested that affects the processing of depression. There is renewed interest in berberine owing to its anti-inflammatory effects. Herein, we investigated whether berberine attenuate depressive-like behaviors via inhibiting NLRP3 inflammasome activation in mice model of depression. METHODS: Adult male C57BL/6N mice were administrated corticosterone (CORT, 20 mg/kg/day) for 35 days. Two doses (100 mg/kg/day and 200 mg/kg/day) of berberine were orally administrated from day 7 until day 35. Behavioral tests were performed to measure the depression-like behaviors alterations. Differentially expressed gene analysis was performed for RNA-sequencing data in the prefrontal cortex. NLRP3 inflammasome was measured by quantitative reverse transcription polymerase chain reaction, western blotting, and immunofluorescence labeling. The neuroplasticity and synaptic function were measured by immunofluorescence labeling, Golgi-Cox staining, transmission electron microscope, and whole-cell patch-clamp recordings. RESULTS: The results of behavioral tests demonstrated that berberine attenuated the depression-like behaviors induced by CORT. RNA-sequencing identified that NLRP3 was markedly upregulated after long-term CORT exposure. Berberine reversed the concentrations of peripheral and brain cytokines, NLRP3 inflammasome elicited by CORT in the prefrontal cortex and hippocampus were decreased by berberine. In addition, the lower frequency of neuronal excitation as well as the dendritic spine reduction were reversed by berberine treatment. Together, berberine increases hippocampal adult neurogenesis and synaptic plasticity induced by CORT. CONCLUSION: The anti-depressants effects of berberine were accompanied by reduced the neuroinflammatory response via inhibiting the activation of NLRP3 inflammasome and rescued the neuronal deterioration via suppression of impairments in synaptic plasticity and neurogenesis.
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Berberina , Doenças Neuroinflamatórias , Masculino , Camundongos , Animais , Camundongos Endogâmicos C57BL , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Depressão , Plasticidade NeuronalRESUMO
BACKGROUND: Converging evidence suggests that stress alters behavioural responses in a sex-specific manner; however, the underlying molecular mechanisms of stress remain largely unknown. METHODS: We adapted unpredictable maternal separation (UMS) and adult restraint stress (RS) paradigms to mimic stress in rats in early life or adulthood, respectively. The sexual dimorphism of the prefrontal cortex was noted, and we performed RNA sequencing (RNA-Seq) to identify specific genes or pathways responsible for sexually dimorphic responses to stress. We then performed quantitative reverse transcription polymerase chain reaction (qRT-PCR) to verify the results of RNA-Seq. RESULTS: Female rats exposed to either UMS or RS showed no negative effects on anxiety-like behaviours, whereas the emotional functions of the PFC were impaired markedly in stressed male rats. Leveraging differentially expressed genes (DEG) analyses, we identified sex-specific transcriptional profiles associated with stress. There were many overlapping DEGs between UMS and RS transcriptional data sets, where 1406 DEGs were associated with both biological sex and stress, while only 117 DEGs were related to stress. Notably, Uba52 and Rpl34-ps1 were the first-ranked hub gene in 1406 and 117 DEGs respectively, and Uba52 was higher than Rp134-ps1, suggesting that stress may have led to a more pronounced effect on the set of 1406 DEGs. Pathway analysis revealed that 1406 DEGs were primarily enriched in ribosomal pathway. These results were confirmed by qRT-PCR. LIMITATIONS: Sex-specific transcriptional profiles associated with stress were identified in this study, but more in-depth experiments, such as single-cell sequencing and manipulation of male and female gene networks in vivo, are needed to verify our findings. CONCLUSION: Our findings show sex-specific behavioural responses to stress and highlight sexual dimorphism at the transcriptional level, shedding light on developing sex-specific therapeutic strategies for stress-related psychiatric disorders.
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Privação Materna , Córtex Pré-Frontal , Animais , Feminino , Masculino , Ratos , Ansiedade/genética , Transtornos de Ansiedade , Perfilação da Expressão Gênica , Córtex Pré-Frontal/metabolismo , Caracteres Sexuais , Transcrição GênicaRESUMO
Oxidative stress is a phenomenon caused by an imbalance between the production and accumulation of reactive oxygen species in cells and tissues that eventually leads to the production of various diseases. Here, we investigated the antioxidant effects of the extract from Sonchus brachyotus DC. (SBE) based on the 0.2% oxazolone-induced intestinal oxidative stress model of zebrafish. Compared to the model group, the treatment group alleviated oxazolone-induced intestinal tissue damage and reduced the contents of malondialdehyde, reactive oxygen species, IL-1ß, and TNF-α and then increased the contents of superoxide dismutase, glutathione peroxidase, and IL-10. The 16s rDNA gene sequencing findings demonstrated that SBE could increase the relative abundance of Fusobacteriota, Actinobacteriota, and Firmicutes and decrease the relative abundance of Proteobacteria. Based on the correlation analysis between the oxidative stress biomarkers and intestinal flora, we found that the trends of oxidative stress biomarkers were significantly correlated with intestinal microorganisms, especially at the genus level. The correlations of MDA, IL-1ß, and TNF-α were significantly negative with Shewanella, while SOD, GSH-Px, and IL-10 were significantly positive with Cetobacterium, Gemmobacter, and Flavobacterium. Consequently, we concluded that the antioxidant effect of SBE was realized through the interaction between oxidative stress biomarkers and gut microbiota.
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In this paper, the reaction mechanism for the adsorption of Zn2+ by synthetic triclinic Na-birnessite was studied by reacting synthetic triclinic Na-birnessite with Zn2+ in solution, thereby providing a theoretical basis for the purification of heavy metal ions in acid soil and water by triclinic birnessite. The adsorption effect of Zn2+ on Na-birnessite enhances with an increase in either reaction time or Na-birnessite dosage, as well as decrease of pH. Na-birnessite can effectively adsorb Zn2+ in acidic solutions without any secondary pollution, and the stronger the acidity, the better the treatment effect. In acidic conditions, H+ in solution exchanges with Na+ in the interlayer of triclinic Na-birnessite, then a small part of Zn2+ in solution exchanges with the Mn2+ produced during the triclinic-to-hexagonal phase transformation, and most of the Zn2+ forms a complex with OH- on the octahedral layer, which loses protons due to the consumption of H+ ions. Finally, Zn2+ adsorbs above and below octahedral vacancies in hexagonal birnessite in either an octahedral or tetrahedral coordination.
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Metais Pesados , Óxidos , Adsorção , Oxirredução , ZincoRESUMO
Early-life stress is normally thought of as a major risk for psychiatric disorders, but many researchers have revealed that adversity early in life may enhance stress resilience later in life. Few studies have been performed in rodents to address the possibility that exposure to early-life stress may enhance stress resilience, and the underlying neural mechanisms are far from being understood. Here, we established a "two-hit" stress model in rats by applying two different early-life stress paradigms: predictable and unpredictable maternal separation (MS). Predictable MS during the postnatal period promotes resilience to adult restraint stress, while unpredictable MS increases stress susceptibility. We demonstrate that structural and functional impairments occur in glutamatergic synapses in pyramidal neurons of the medial prefrontal cortex (mPFC) in rats with unpredictable MS but not in rats with predictable MS. Then, we used differentially expressed gene (DEG) analysis of RNA sequencing data from the adult male PFC to identify a hub gene that is responsible for stress resilience. Oxytocin, a peptide hormone, was the highest ranked differentially expressed gene of these altered genes. Predictable MS increases the expression of oxytocin in the mPFC compared to normal raised and unpredictable MS rats. Conditional knockout of the oxytocin receptor in the mPFC was sufficient to generate excitatory synaptic dysfunction and anxiety behavior in rats with predictable MS, whereas restoration of oxytocin receptor expression in the mPFC modified excitatory synaptic function and anxiety behavior in rats subjected to unpredictable MS. These findings were further supported by the demonstration that blocking oxytocinergic projections from the paraventricular nucleus of the hypothalamus (PVN) to the mPFC was sufficient to exacerbate anxiety behavior in rats exposed to predictable MS. Our findings provide direct evidence for the notion that predictable MS promotes stress resilience, while unpredictable MS increases stress susceptibility via mPFC oxytocin signaling in rats.
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Privação Materna , Ocitocina , Animais , Ansiedade/metabolismo , Masculino , Ocitocina/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Transdução de Sinais , Estresse PsicológicoRESUMO
Ischemic stroke is a common type of cerebrovascular event and also the leading cause of disability. Post-stroke cognitive impairment occurs frequently in stroke survivors. Shexiang Baoxin Pill (SBP) is a proprietary Chinese medicine, initially used to treat cardiovascular diseases. Herein, we aim to explore the effects of SBP on oxygen glucose deprivation and reoxygenation (OGD/R) in neuronal cells (CATH.a) and cerebral ischemia/reperfusion injury induced post-stroke cognitive impairment in middle cerebral artery occlusion (MCAO) rat model. MCAO rats received two doses of oral SBP treatment (28 or 56 mg/kg) after 1 h of operation and once daily for 2 weeks continuously. Behavioral tests, immunoblotting, and immunofluorescence were examined after 14 days. Current data suggest that SBP enhanced cell viability and downregulated apoptosis via activating the PI3K/Akt signaling pathway in CATH. a cells. Furthermore, 14 days of SBP treatment promoted the recovery of learning and locomotor function in the MCAO rats. SBP up-regulated the expression of p-Akt, p-GSK3ß, as well as the expression of NMDAR1, PSD-95, and AMPAR. Also, SBP down-regulated the expression of p-CaMKII. These results indicated that long-term SBP treatment might be a potential option for cognitive impairment induced by the ischemic stroke.
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Circulating tumor cells (CTCs), as the precursor of metastases, gain mesenchymal traits through the epithelialmesenchymal transition (EMT) process, thereby mediating tumor metastasis. However, the dynamic changes and clinical value of mesenchymal CTCs (MCTCs) in colorectal cancer (CRC) patients remain inconclusive. The aim of the present study was to explore the prognostic value of dynamic changes of MCTCs in CRC patients using our previously developed CTCBIOPSY® device with an immunocytochemistry assay. The results revealed that 74 out of 175 patients were preMCTCspositive and 41 out of 127 patients were postMCTCspositive. Dynamical monitoring revealed that the status of MCTCs remained dynamically changed under the pressure of anticancer therapy, and these dynamic changes were significantly associated with lymphovascular invasion (P<0.001) and TNM stage (P=0.033). Moreover, KaplanMeier survival analyses revealed that the median recurrencefree survival (RFS) and overall survival (OS) were significantly different between four groups (preMCTCâpostMCTC; preMCTCâpostMCTC+; preMCTC+âpostMCTC; preMCTC+âpostMCTC+), and patients with preMCTCs+âpostMCTCs+ had a significant shorter RFS (P=0.001) and OS (P<0.001) than the others. Univariate and multivariate Cox regression analyses demonstrated that persistent positivity of MCTCs before and after anticancer therapy was an independent risk factor affecting the RFS (HR: 1.302, 95%CI: 1.0331.639, P=0.025) and OS (HR: 1.366, 95%CI: 1.0701.742, P=0.012) of CRC patients. Collectively, these findings provided the evidence that the dynamic change of MCTCs during anticancer therapy can be a useful prognostic tool in CRC, indicating the important value of molecular profiling of CTCsEMT traits in cancer management.
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Neoplasias Colorretais/terapia , Recidiva Local de Neoplasia/epidemiologia , Células Neoplásicas Circulantes/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Contagem de Células , Quimioterapia Adjuvante/métodos , Colo/patologia , Colo/cirurgia , Neoplasias Colorretais/sangue , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Reto/patologia , Reto/cirurgiaRESUMO
In recent years, the fingerprint of high-performance liquid chromatography has been extensively applied in the identification and quality control of traditional Chinese medicine. It can be a potential protocol for assessing the authenticity, stability and consistency of traditional Chinese medicine and guaranteeing the expected biological activity. In this paper, a method using high-performance liquid chromatography to identify and control the quality of the extract of Taraxacum mongolicum Hand.-Mazz. (TME) was established. With this method, the correlation coefficients of the similarity of 10 batches were ≥0.994. The TME displayed a steady proliferative effect in Lactobacillus plantarum. In brief, this study successfully built a reliable, simple and efficient method to control and confirm the quality and the stability of biological activity of the TME.
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Proliferação de Células/efeitos dos fármacos , Lactobacillus plantarum/efeitos dos fármacos , Extratos Vegetais , Taraxacum/química , Cromatografia Líquida de Alta Pressão , Extratos Vegetais/análise , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/normas , Controle de Qualidade , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Menopause is closely associated with the risk of anxiety and depression in a woman's life. Despite the numerous reports on the effects of Radix rehmanniae extract (RRE) on various types of depression, there are few studies exploring the effects of RRE on the menopausal anxiety and depression. PURPOSE: To investigate whether RRE could alleviate the menopausal anxiety and depression in ovariectomized (OVX) mice submitted to chronic unpredictable mild stress (CUMS). METHODS: OVX mice were treated with 2.6â¯g/kg RRE for 5 weeks. After a series of behavior tests, serum, uterus, and brain tissues were collected for the measurement of neurotransmitters and their related biomarkers, neurotrophins, and estrogen receptor α (ERα) and ß (ERß). RESULTS: RRE showed antidepressant and anxiolytic effects through these behavior tests, but had no effects on the OVX-induced weight gains, uterine shrinkage and drop of serum estrogen level. RRE restored the levels of serotonin (5-HT), dopamine (DA) and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), Glutamate (Glu), gamma-Aminobutyric acid (GABA) and their related biomarkers in different brain regions. RRE also reversed OVX-induced decrease in the expression levels of neurotrophins in uterus and brain regions except for uterine nerve growth factor (NGF). Moreover, RRE restored and even enhanced ERß expression levels in uterus and brain without affecting uterine, hippocampal and cortical ERα. CONCLUSION: This study demonstrated the antidepressant and anxiolytic effects of RRE in OVX mice, which were possibly mediated via their modulation of brain neurotransmitters, and regulation of neurotrophins and activation of ERß.
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Antidepressivos/farmacologia , Transtornos de Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Orobanchaceae/química , Extratos Vegetais/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressão/metabolismo , Dopamina/metabolismo , Estradiol/sangue , Feminino , Menopausa/psicologia , Camundongos Endogâmicos C57BL , Neurotransmissores/metabolismo , Ovariectomia/efeitos adversos , Receptores de Estrogênio/metabolismo , Serotonina/metabolismo , Útero/efeitos dos fármacosRESUMO
BACKGROUND: Lily bulb is often used as a dietary supplement for menopause. This study was aimed to investigate the ameliorative effects of aqueous extract of lily bulb (AELB) on the menopause-associated psychiatric disorders and the underlying mechanisms in comparison with estrogen therapy. METHODS: Ovariectomized (OVX) mice were treated with 1.8â¯g/kg AELB or 0.3â¯mg/kg estradiol for 5 weeks. Animals were tested in multiple behavioral paradigms. Serum, uterus, and brain tissues were collected for the measurement of neurotransmitters and their related biomarkers, neurotrophins, and estrogen receptor α (ERα) and ß (ERß). RESULTS: AELB and estradiol had similar anxiolytic, antidepressant, and cognition-improving effects. While estradiol limited OVX-induced weight gains and prevented uterine shrinkage and the drop of serum estrogen level, AELB had minor and even no effects on these indices. AELB, but not estradiol, reversed OVX-induced decreases in the expression levels of hippocampal nerve growth factor (NGF) and prefrontal glial cell-derived neurotrophic factor (GDNF). In addition to hypothalamic and prefrontal ERα, AELB enhanced uterine and brain regional ERß expression levels without affecting uterine ERα, NGF, and GDNF. Conversely, estradiol completely restored the expression levels of estrogen receptors and neurotrophins in uterus. CONCLUSIONS: While AELB is comparable to estradiol in alleviating menopause-like behavior, it has distinct brain-uterus mechanisms in association with the predominant protection of catecholamine synthesis, neurotrophins, and ERß receptors in brain, but with minor effects on uterus. AELB and its constituents may be novel treatments for menopause.
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Comportamento Animal , Encéfalo/fisiologia , Estrogênios/uso terapêutico , Lilium/química , Menopausa/efeitos dos fármacos , Ovariectomia , Extratos Vegetais/farmacologia , Útero/fisiologia , Animais , Ansiedade/complicações , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Cognição , Depressão/complicações , Dopamina/metabolismo , Estradiol/sangue , Feminino , Terapia de Reposição Hormonal , Menopausa/sangue , Metaboloma , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Serotonina/metabolismo , Útero/efeitos dos fármacos , ÁguaRESUMO
Chemotherapy-induced cognitive impairment, also known as "chemobrain," is a common side effect. The purpose of this study was to examine whether ginsenoside Rg1, a ginseng-derived compound, could prevent chemobrain and its underlying mechanisms. A mouse model of chemobrain was developed with three injections of docetaxel, adriamycin, and cyclophosphamide (DAC) in combination at a 2-day interval. Rg1 (5 and 10 mg/kg daily) was given 1 week prior to DAC regimen for 3 weeks. An amount of 10 mg/kg Rg1 significantly improved chemobrain-like behavior in water maze test. In vivo neuroimaging revealed that Rg1 co-treatment reversed DAC-induced decreases in prefrontal and hippocampal neuronal activity and ameliorated cortical neuronal dendritic spine elimination. It normalized DAC-caused abnormalities in the expression of multiple neuroplasticity biomarkers in the two brain regions. Rg1 suppressed DAC-induced elevation of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), but increased levels of the anti-inflammatory cytokines IL-4 and IL-10 in multiple sera and brain tissues. Rg1 also modulated cytokine mediators and inhibited DAC-induced microglial polarization from M2 to M1 phenotypes. In in vitro experiments, while impaired viability of PC12 neuroblastic cells and hyperactivation of BV-2 microglial cells, a model of neuroinflammation, were observed in the presence of DAC, Rg1 co-treatment strikingly reduced DAC's neurotoxic effects and neuroinflammatory response. These results indicate that Rg1 exerts its anti-chemobrain effect in an association with the inhibition of neuroinflammation by modulating microglia-mediated cytokines and the related upstream mediators, protecting neuronal activity and promoting neuroplasticity in particular brain regions associated with cognition processing.
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Antineoplásicos/efeitos adversos , Encéfalo/patologia , Disfunção Cognitiva/prevenção & controle , Citocinas/metabolismo , Ginsenosídeos/uso terapêutico , Inflamação/tratamento farmacológico , Microglia/patologia , Plasticidade Neuronal , Animais , Ansiedade/complicações , Ansiedade/fisiopatologia , Comportamento Animal , Biomarcadores/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Cognição/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/fisiopatologia , Citocinas/sangue , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Feminino , Ginsenosídeos/farmacologia , Proteína Glial Fibrilar Ácida/metabolismo , Inflamação/sangue , Inflamação/complicações , Inflamação/patologia , Locomoção/efeitos dos fármacos , Imageamento por Ressonância Magnética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Células PC12 , RatosRESUMO
Depression and anxiety often co-occur with cardiac diseases. The Shexiang Baoxin pill (SBP) is a proprietary Chinese medicine initially used to treat cardiac conditions. This study explored whether SBP has antidepressant and anxiolytic effects in addition to hormonal and psychotropic mechanisms. Mice underwent 6 weeks of chronic unpredictable mild stress (CUMS) to induce depression- and anxiety-like behavior. During the 6-week experiment, mice received SBP at intragastric doses of 20.25 mg/kg or 40.5 mg/kg daily. Animals were then tested for depression in sucrose preference, forced-swimming, and tail suspension paradigms, and for anxiety in open field and elevated plus maze tests. Both SBP doses significantly reduced anhedonic behavior in the sucrose preference test; the high SBP dose also increased the number of entries into the central zone of the open field. SBP-treated mice had markedly lower blood levels of corticotrophin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) than stressed mice treated with vehicle. Either low- or high-dose SBP reversed stress-induced reductions of norepinephrine (NE) and dopamine (DA) metabolites and the expression levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell-derived neurotrophic factor (GDNF) in related brain regions. These results suggest that SBP could prevent and alleviate prolonged stress-induced anhedonia and anxiety in association with its suppression of the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, modulation of brain monoamine neurotransmitter metabolism and neurotrophins. SBP may be particularly suitable for the management of depressive and anxiety disorders in patients with cardiac conditions.
Assuntos
Ansiolíticos/administração & dosagem , Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Animais , Fator Neurotrófico Derivado do Encéfalo , Depressão/psicologia , Modelos Animais de Doenças , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismoRESUMO
Chemotherapy-induced cognitive impairment, often referred to as "chemobrain," is a common side effect. In this study, mice received three intraperitoneal injections of a combination of docetaxel, adriamycin, and cyclophosphamide (DAC) at 2-day intervals. A water maze test was used to examine cognitive performance, and manganese-enhanced magnetic resonance imaging (MEMRI) was used to examine hippocampal neuronal activity. The whole brain, prefrontal cortex, hippocampus, and blood samples were then collected for cytokine measurement. The DAC-treated mice displayed a significantly shorter duration spent in and fewer entries into the target quadrant of the water maze than the control mice and a pronounced decrease in MEMRI signal intensity in the hippocampal subregions. In a separate experiment using in vivo transcranial two-photon imaging, DAC markedly eliminated dendritic spines without changing the rate of spine formation, leading to a striking loss of spines in the medial prefrontal cortex. DAC treatment resulted in significant elevations in the levels of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) and in significant decreases in the levels of the anti-inflammatory cytokines IL-4 and IL-10 in most of the sera and brain tissues examined. The IL-6 and TNF-α levels of several sera and brain tissues showed strong inverse correlations with the duration and number of entries in the target quadrant of the water maze and with the hippocampal MEMRI signal intensity, but also showed striking positive correlations with spine elimination and loss. These results indicate that chemobrain is associated with cytokine dysregulation and disrupted neuroplasticity of the brain.