RESUMO
SUMMARY: We evaluated the role and mechanism of acteoside in the regulation of memory impairment induced by chronic unpredictable mild stress (CUMS). CUMS was used to induce depression in rats and the successful establishment of CUMS model were verified by forced swimming test and sucrose preference test. The Y-maze test and novel object recognition test assessed memory functions. The structural changes in the cortex and hippocampus were observed by hematoxylin and eosin (HE) staining. Immunofluorescence staining and western blotting determined the protein levels. Y-maze test and novel object recognition test showed that there was memory performance impairment in rats of CUMS group, which was improved by the acteoside treatment. HE staining showed that CUMS exposure damaged the structure in the cortex and hippocampus, while the acteoside treatment alleviated the structural changes. Compared with the control group, the levels of BNDF and CREB in the cortex and hippocampus of the CUMS group were significantly decreased. Acteoside significantly reversed the expressions of these proteins in CUMS rats. Meanwhile, compared with the control group, the levels of p-mTOR and p- P70S6K in the cortex and hippocampus of the CUMS group were significantly increased, and these changes were significantly reversed by acteoside. Nevertheless, the effect of acteoside on mTOR signaling was markedly blocked by rapamycin, a specific inhibitor of mTOR signaling. Acteoside can attenuate memory impairment and ameliorate neuronal damage and synaptic plasticity in depression rats probably via inhibiting the mTOR signaling pathway. Acteoside may serve as a novel reagent for the prevention of depression.
Evaluamos el papel y el mecanismo del acteoside en la regulación del deterioro de la memoria inducido por estrés leve crónico impredecible (ELCI). Se utilizó ELCI para inducir depresión en ratas y el establecimiento exitoso del modelo ELCI se verificó mediante una prueba de natación forzada y una prueba de preferencia de sacarosa. La prueba del laberinto en Y y la prueba de reconocimiento de objetos novedosos evaluaron las funciones de la memoria. Los cambios estructurales en la corteza y el hipocampo se observaron mediante tinción con hematoxilina y eosina (HE). La tinción por inmunofluorescencia y la transferencia Western determinaron los niveles de proteína. La prueba del laberinto en Y y la prueba de reconocimiento de objetos novedosos mostraron que había un deterioro del rendimiento de la memoria en ratas del grupo ELCI, que mejoró con el tratamiento con acteósidos. La tinción con HE mostró que la exposición a ELCI dañó la estructura de la corteza y el hipocampo, mientras que el tratamiento con actósidos alivió los cambios estructurales. En comparación con el grupo de control, los niveles de BNDF y CREB en la corteza y el hipocampo del grupo ELCI disminuyeron significativamente. Acteoside revirtió significativamente las expresiones de estas proteínas en ratas ELCI. Mientras tanto, en comparación con el grupo control, los niveles de p-mTOR y p-P70S6K en la corteza y el hipocampo del grupo ELCI aumentaron significativamente, y estos cambios fueron revertidos significativamente ELCI por el acteoside. Sin embargo, el efecto del acteoside sobre la señalización de mTOR fue notablemente bloqueado por la rapamicina, un inhibidor específico de la señalización de mTOR. El acteoside puede atenuar el deterioro de la memoria y mejorar el daño neuronal y la plasticidad sináptica en ratas con depresión, probablemente mediante la inhibición de la vía de señalización mTOR. Acteoside puede servir como un reactivo novedoso para la prevención de la depresión.
Assuntos
Animais , Ratos , Depressão/tratamento farmacológico , Polifenóis/administração & dosagem , Glucosídeos/administração & dosagem , Transtornos da Memória/tratamento farmacológico , Estresse Psicológico/complicações , Western Blotting , Imunofluorescência , Ratos Sprague-Dawley , Aprendizagem em Labirinto , Reconhecimento Psicológico/efeitos dos fármacos , Modelos Animais de Doenças , Serina-Treonina Quinases TOR/antagonistas & inibidores , Polifenóis/uso terapêutico , Escala de Avaliação Comportamental , Inibidores de MTOR , Glucosídeos/uso terapêutico , Plasticidade Neuronal/efeitos dos fármacos , NeurôniosRESUMO
The most widely prescribed antidepressant, fluoxetine (FLX), is known for its antioxidant and anti-inflammatory effects when administered post-stress. Few studies have evaluated the effects of FLX treatment when chronic stress has induced deleterious effects in patients. Our objective was to evaluate FLX treatment (20 mg/kg/day, i.v.) once these effects are manifested, and the drug's relation to extracellular circulating microRNAs associated with inflammation, a hedonic response (sucrose intake), the forced swim test (FST), and corticosterone levels (CORT) and monoamine concentrations in limbic areas. A group of Wistar rats was divided into groups: Control; FLX; CUMS (for six weeks of exposure to chronic, unpredictable mild stress); and CUMS + FLX, a mixed group. After CUMS, the rats performed the FST, and serum levels of CORT and six microRNAs (miR-16, -21, -144, -155, -146a, -223) were analyzed, as were levels of dopamine, noradrenaline, and serotonin in the prefrontal cortex, hippocampus, and hypothalamus. CUMS reduced body weight, sucrose intake, and hippocampal noradrenaline levels, but increased CORT, immobility behavior on the FST, dopamine concentrations in the prefrontal cortex, and all miRNAs except miR-146a expression. Administering FLX during CUMS reduced CORT levels and immobility behavior on the FST and increased the expression of miR-16, -21, -146a, -223, and dopamine. FLX protects against the deleterious effects of stress by reducing CORT and has an antidepressant effect on the FST, with minimally-modified neurotransmitter levels. FLX increased the expression of miRNAs as part of the antidepressant effect. It also regulates both neuroinflammation and serotoninergic neurotransmission through miRNAs, such as the miR-16.
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Inflammatory processes play a pivotal role in the development and progression of depression. Since Follistatin-like protein 1 (FSTL1) has been identified as a novel inflammatory protein, a variety of studies suggest that targeting FSTL1 may be useful in the treatment of diseases in which inflammation plays a central role. In the study, we aimed to investigate the causal relationship between FSTL1 signaling and the development of depression. To explore the effect and mechanism of FSTL1 on chronic stress-induced depression, the chronic unpredictable mild stress (CUMS) paradigm was used. Animals subjected to CUMS for 4 weeks exhibited depressive-like symptoms, including decreased sucrose preference and obvious behavioral despair, concomitantly with increased FSTL1 level in the hippocampus. In contrast, mice with FSTL1 knockdown abolished CUMS induced depression-like and anxiety-like behaviors. Moreover, FSTL1 knockdown reversed CUMS induced synaptic plasticity deficits in the PP-DG pathway of the hippocampus and increased the expression of synaptic associated proteins in the hippocampus of CUMS exposed mice. Microglia activation induced by CUMS paradigm could be significantly inhibited by FSTL1 knockdown. Furthermore, Western blot revealed that FSTL1 knockdown considerably decreased the expression of indicated molecules TLR4/MyD88/NF-κB signaling pathway in CUMS exposed mice. In conclusion, our data implies that FSTL1 may modulate the microglial activation through TLR4/MyD88/NF-κB signaling, which affects depression-like behaviors and synaptic function deficits induced by CUMS in mice. These results suggested that the role of FSTL1 in mediating microglia-related mechanisms in depression may shed light on developing new therapeutic strategies to treat this prevalent disease.
Assuntos
Proteínas Relacionadas à Folistatina/metabolismo , NF-kappa B , Animais , Depressão/metabolismo , Modelos Animais de Doenças , Proteínas Relacionadas à Folistatina/genética , Hipocampo/metabolismo , Camundongos , Microglia/metabolismo , Fator 88 de Diferenciação Mieloide , NF-kappa B/metabolismo , Estresse Psicológico/tratamento farmacológico , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismoRESUMO
Stress-related disorders display differences at multiple levels according to sex. While most studies have been conducted in male rodents, less is known about comparable outcomes in females. In this study, we found that the chronic restraint stress model (2.5 h/day for 14 days) triggers different somatic responses in male and female adult rats. Chronic restraint produced a loss in sucrose preference and novel location preference in male rats. However, chronic restraint failed to produce loss of sucrose preference in females, while it improved spatial performance. We then characterized the molecular responses associated with these behaviors in the hippocampus, comparing the dorsal and ventral poles. Notably, sex- and hippocampal pole-specific transcriptional signatures were observed, along with a significant concordance between the female ventral and male dorsal profiles. Functional enrichment analysis revealed both shared and specific terms associated with each pole and sex. By looking into signaling pathways that were associated with these terms, we found an ample array of sex differences in the dorsal and, to a lesser extent, in the ventral hippocampus. These differences were mainly present in synaptic TrkB signaling, Akt pathway, and glutamatergic receptors. Unexpectedly, the effects of stress on these pathways were rather minimal and mostly dissociated from the sex-specific behavioral outcomes. Our study suggests that female rats are resilient and males susceptible to the restraint stress exposure in the sucrose preference and object location tests, while the activity of canonical signaling pathways is primarily determined by sex rather than stress in the dorsal and ventral hippocampus.
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In the present study, antidepressant-like activity of ethanol extract of leaves of Caesalpinia pulcherrima was evaluated in Swiss young male albino mice. Stress was induced in mice by subjecting them to unpredictable mild stress for 21 successive days. Ethanol extract of the leaves (100, 200 and 400 mg/ kg, p.o.) and fluoxetine (20 mg/kg, p.o.) were administered for 21 consecutive days to separate groups of unstressed and stressed mice. Ethanol extract (200 and 400 mg/kg) and fluoxetine significantly decreased immobility period of unstressed as well as stressed mice in tail suspension test (TST). However, the lowest dose (100 mg/kg) of the extract also significantly decreased immobility period of stressed mice in TST. The extract significantly restored reduced sucrose preference in stressed mice. There was no significant effect on locomotor activity of mice. Ethanol extract of the leaves significantly decreased plasma nitrite and corticosterone levels; brain MAO-A activity and MDA level; and increased brain reduced glutathione and catalase activity in unstressed as well as stressed mice as compared to their respective vehicle treated controls. Thus, ethanol extract of leaves of Caesalpinia pulcherrima showed significant antidepressant-like activity in unstressed and stressed mice probably through inhibition of brain MAO-Aactivity, reduction of oxidative stress and plasma corticosterone levels.
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Animais , Masculino , Camundongos , Extratos Vegetais/análise , Folhas de Planta/classificação , Caesalpinia/efeitos adversos , Etanol , Sacarose , Fluoxetina , Estresse Oxidativo/efeitos dos fármacos , DosagemRESUMO
This study aimed to investigate the antidepressant effect and the mechanism of action of Kai-Xin-San (KXS) in fluoxetine-resistant depressive (FRD) rats. Two hundred male Wistar rats weighing 200±10 g were exposed to chronic and unpredictable mild stresses (CUMS) for 4 weeks and given fluoxetine treatment simultaneously. The rats that did not show significant improvement in behavioral indexes were chosen as the FRD model rats. These rats were randomly divided into four groups: FRD model control; oral fluoxetine and aspirin; oral KXS at a dose of 338 mg·kg-1·day-1; and oral KXS at a dose of 676 mg·kg-1·day-1. Rats continued to be exposed to CUMS and underwent treatment once a day for 3 weeks, then cytokine (COX-2, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-10, TGF-β, and TNF-α) levels in the hippocampus and serum, and organ coefficients were measured. Both doses of KXS improved the crossing and rearing frequencies, sucrose-preference index, and body weight in FRD rats. KXS at a dose of 338 mg·kg-1·day-1reduced COX-2, IL-2, IL-6, TNF-α levels, increased IL-10 level in the hippocampus, and reduced IL-2 and TNF-α levels in serum. KXS at a dose of 676 mg·kg-1·day-1reduced TNF-α level in the hippocampus, reduced IL-2 and TNF-α levels in serum, and increased IFN-γ and IL-10 levels in the hippocampus and serum. There were no significant differences in organ-coefficients of the spleen among and between groups. The results suggested that oral administration of KXS in FRD rats was effective in improving behavior disorders by influencing various inflammatory pathways.
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Animais , Masculino , Ratos , Antidepressivos/uso terapêutico , Citocinas/metabolismo , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Hipocampo/metabolismo , Citocinas/efeitos dos fármacos , Depressão/metabolismo , Modelos Animais de Doenças , Resistência a Medicamentos , Fluoxetina/efeitos adversos , Hipocampo/efeitos dos fármacos , Distribuição Aleatória , Ratos Wistar , Estresse Psicológico/psicologiaRESUMO
Chronic unpredictable mild stress (CUMS) elicits aspects of cognitive and behavioral alterations that can be used to model comparable aspects of depression in humans. The aim of the present study was to investigate the antidepressant-like potential of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a novel isoquinoline compound, in CUMS, a model that meets face, construct and predictive criteria for validity. Swiss mice were subjected to different stress paradigms daily for a period of 35 days to induce the depressive-like behavior. The animals received concomitant FDPI (0.1 and 1mg/kg, intragastric) or paroxetine (8mg/kg, intraperitoneal) and CUMS. The behavioral tests (splash test, tail suspension test, modified forced swimming test and locomotor activity) were performed. The levels of cytokines, corticosterone and adrenocorticotropic (ACTH) hormones were determined in the mouse prefrontal cortex and serum. The synaptosomal [(3)H] serotonin (5-HT) uptake, nuclear factor (NF)-κB, tyrosine kinase receptor (TrkB) and pro-brain-derived neurotrophic factor (BDNF) levels were determined in the mouse prefrontal cortex. CUMS induced a depressive-like behavior in mice, which was demonstrated in the modified forced swimming, tail suspension and splash tests. FDPI at both doses prevented depressive-like behavior induced by CUMS, without altering the locomotor activity of mice. FDPI at the highest dose prevented the increase in the levels of NF-kB, pro-inflammatory cytokines, corticosterone and ACTH and modulated [(3)H]5-HT uptake and the proBDNF/TrkB signaling pathway altered by CUMS. The present findings demonstrated that FDPI elicited an antidepressant-like effect in a model of stress-induced depression.
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Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Depressão/etiologia , Quinolinas/uso terapêutico , Estresse Psicológico/complicações , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Citocinas/metabolismo , Depressão/metabolismo , Modelos Animais de Doenças , Asseio Animal/efeitos dos fármacos , Elevação dos Membros Posteriores/psicologia , Hormônios/metabolismo , Locomoção , Masculino , Camundongos , Paroxetina/uso terapêutico , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Quinolinas/farmacologia , Serotonina/farmacocinética , Natação/psicologia , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Trítio/farmacocinéticaRESUMO
Studies have indicated that early-life or early-onset depression is associated with a 2- to 4-fold increased risk of developing Alzheimers disease (AD). In AD, aggregation of an abnormally phosphorylated form of the tau protein may be a key pathological event. Tau is known to play a major role in promoting microtubule assembly and stabilization, and in maintaining the normal morphology of neurons. Several studies have reported that stress may induce tau phosphorylation. The main aim of the present study was to investigate possible alterations in the tau protein in the hippocampus and frontal cortex of 32 male Sprague-Dawley rats exposed to chronic unpredictable mild stress (CUMS) and then re-exposed to CUMS to mimic depression and the recurrence of depression, respectively, in humans. We evaluated the effects of CUMS, fluoxetine, and CUMS re-exposure on tau and phospho-tau. Our results showed that a single exposure to CUMS caused a significant reduction in sucrose preference, indicating a state of anhedonia. The change in behavior was accompanied by specific alterations in phospho-tau protein levels, but fluoxetine treatment reversed the CUMS-induced impairments. Moreover, changes in sucrose preference and phospho-tau were more pronounced in rats re-exposed to CUMS than in those subjected to a single exposure. Our results suggest that changes in tau phosphorylation may contribute to the link between depression and AD.