RESUMO
BACKGROUND: Excessive stress, a major problem in modern societies, affects people of all ages worldwide. Corticosterone is one of the most abundant hormones secreted during stressful conditions and is associated with various dysfunctions in the body. In particular, we aimed to investigate the protective effects of hygrolansamycin C (HYGC) against corticosterone-induced cellular stress, a manifestation of excessive stress prevalent in contemporary societies. METHODS: We isolated HYGC from Streptomyces sp. KCB17JA11 and subjected PC12 cells to corticosterone-induced stress. The effects of HYGC were assessed by measuring autophagy and the expression of mitogen-activated protein kinase (MAPK) phosphorylation-related genes. We used established cellular and molecular techniques to analyze protein levels and pathways. RESULTS: HYGC effectively protected cells against corticosterone-induced injury. Specifically, it significantly reduced corticosterone-induced oxidative stress and inhibited the expression of autophagy-related proteins induced by corticosterone, which provided mechanistic insight into the protective effects of HYGC. At the signaling level, HYGC suppressed c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation and p38 activation. CONCLUSIONS: HYGC is a promising candidate to counteract corticosterone-induced apoptosis and oxidative stress. Autophagy and MAPK pathway inhibition contribute to the protective effects of HYGC. Our findings highlight the potential of HYGC as a therapeutic agent for stress-related disorders and serve as a stepping stone for further exploration and development of stress management strategies.
Assuntos
Corticosterona , Proteínas Quinases p38 Ativadas por Mitógeno , Ratos , Animais , Humanos , Corticosterona/toxicidade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , Estresse Oxidativo , Transdução de Sinais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Apoptose , AutofagiaRESUMO
The hypothalamic-pituitary-adrenal (HPA) system plays an important role in stress response. Chronic stress is thought to induce neuronal damage and contribute to the pathogenesis of psychiatric disorders by causing dysfunction of the HPA system and promoting the production and release of glucocorticoids, including corticosterone and cortisol. Several clinical studies have demonstrated the efficacy of herbal medicines in treating psychiatric disorders; however, their effects on corticosterone-induced neuronal cell death remain unclear. Here, we used HT22 cells to evaluate the neuroprotective potential of herbal medicines used in neuropsychiatry against corticosterone-induced hippocampal neuronal cell death. Cell death was assessed using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) reduction and Live/Dead assays. Hangekobokuto, Kamikihito, Saikokaryukotsuboreito, Kamishoyosan, and Yokukansan were supplied in the form of water-extracted dried powders. Exposure of HT22 cells to ≥ 100 µM corticosterone decreased MTT values. Exposure to 500 µM corticosterone alone reduced MTT values to 18%, while exposure to 10 µM Mifepristone (RU486)-a glucocorticoid receptor antagonist-restored values to 36%. Corticosterone-induced cell death was partially suppressed by treatment with RU486. At 100 µg/mL, Hangekobokuto significantly suppressed the decrease in MTT values (15-32%) and increase in the percentage of ethidium homodimer-1-positive dead cells caused by corticosterone exposure (78-36%), indicating an inhibitory effect on cell death. By contrast, Kamikihito, Saikokaryukotsuboreito, Kamishoyosan, and Yokukansan did not affect corticosterone-induced cell death. Therefore, our results suggest that Hangekobokuto may ameliorate the onset and progression of psychiatric disorders by suppressing neurological disorders associated with increased levels of glucocorticoids.
Assuntos
Corticosterona , Mifepristona , Humanos , Corticosterona/toxicidade , Corticosterona/metabolismo , Mifepristona/farmacologia , Glucocorticoides , Sistema Hipotálamo-Hipofisário/metabolismo , Morte Celular , Sistema Hipófise-Suprarrenal/metabolismoRESUMO
Lilii Bulbus is a folk medicine for both culinary and medicinal purpose. In traditional medicine theory, Lilii Bulbus is usually used as an complementary therapy for nourishing the heart and lung, clearing heat in the treatment of mental instability and depression. In this study, NLPS-1a (Mw = 2610 Da, DP = 16), a water-soluble non-starch Lilii Bulbus polysaccharides, was isolated and purified. Structural analysis showed that NLPS-1a mainly contained Man and Glc with a molar ratio of 11.137 and 9.427. The glycosidic linkages of NLPS-1a were 1,3-Manp (59.93%), 1,2-Glcp (37.93%), T-Glcp (1.21%) and T-Manp (0.93%), indicating the highly-linear structures. In addition, NLPS-1a could significantly repair the injury of PC12 cells induced by corticosterone (CORT), reduce Lactate dehydrogenase (LDH) leakage and decrease the cell apoptosis in a dose-dependent manner. Above all, the results indicated that NLPS-1a had protective effects against CORT-induced neurotoxicity in PC12 cells, and might be a natural antidepressant, which enriched the study of the metabolic mechanism between herbal polysaccharides and antidepressant.
Assuntos
Apoptose , Corticosterona , Ratos , Animais , Humanos , Corticosterona/toxicidade , Células PC12 , Polissacarídeos/farmacologia , Antidepressivos/farmacologiaRESUMO
BACKGROUND: Corticosterone (CORT) can induce neuronal damage in various brain regions, including the cerebral cortex, the region implicated in depression. However, the underlying mechanisms of these CORT-induced effects remain poorly understood. Recently, many studies have suggested that adipose stem cell-derived extracellular vesicles (A-EVs) protect neurons in the brain. METHODS: To investigated neuroprotection effects of A-EVs in the CORT-induced cortical neurons, we cultured cortical neurons from E15 mice for 7 days, and the cultured cortical neurons were pretreated with different numbers (5 × 105-107 per mL) of A-EVs (A-EVs5, A-EVs6, A-EVs7) for 30 min followed by administration of 200 µM CORT for 24 h. RESULTS: Here, we show that A-EVs exert antiapoptotic effects by inhibiting endoplasmic reticulum (ER) stress in CORT-induced cortical neurons. We found that A-EVs prevented neuronal cell death induced by CORT in cultured cortical neurons. More importantly, we found that CORT exposure in cortical neurons resulted in increased levels of apoptosis-related proteins such as cleaved caspase-3. However, pretreatment with A-EVs rescued the levels of caspase-3. Intriguingly, CORT-induced apoptosis involved upstream activation of ER stress proteins such as GRP78, CHOP and ATF4. However, pretreatment with A-EVs inhibited ER stress-related protein expression. CONCLUSION: Our findings reveal that A-EVs exert antiapoptotic effects via inhibition of ER stress in CORT-induced cell death.
Assuntos
Corticosterona , Vesículas Extracelulares , Animais , Apoptose , Córtex Cerebral , Corticosterona/metabolismo , Corticosterona/toxicidade , Vesículas Extracelulares/metabolismo , Camundongos , Neurônios/metabolismo , Células-TroncoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Jiao-Tai-Wan (JTW) is a very famous traditional Chinese medicine formula for the treatment of psychiatric disorders, especially in anxiety, insomnia and depression. However, its molecular mechanism of treatment remains indistinct. AIM OF THE STUDY: We aimed to reveal the action mechanism of JTW on anti-depression via inhibiting microglia activation and pro-inflammatory response both in vivo and in vitro. MATERIAL AND METHODS: The corticosterone (CORT)-induced depression mouse model was used to evaluate the therapeutic efficacy of JTW. Behavioral tests (open field, elevated plus maze, tail suspension and forced swim test) were conducted to evaluate the effect of JTW on depressive-like behaviors. The levels of inflammatory factors and the concentration of neurotransmitters were detected by RT-qPCR or ELISA assays. Then three hippocampal tissue samples per group (Control, CORT, and JTW group) were sent for RNA sequencing (RNA-seq). Transcriptomics data analysis was used to screen the key potential therapeutic targets and signaling pathways of JTW. Based on 8 bioactive species of JTW by our previous study using High-performance liquid chromatography (HPLC) analysis, molecular docking analyses were used to predict the interaction of JTW-derived compounds and depression targets. Finally, the results of transcriptome and molecular docking analyses were combined to verify the targets, key pathways, and efficacy of JTW treatment in vivo and vitro. RESULTS: JTW ameliorated CORT-induced depressive-like behaviors, neuronal damage and enhanced the levels of monoamine neurotransmitters in the serum of mice. JTW also inhibited CORT-induced inflammatory activation of microglia and decreased the serum levels of interleukin- 6(IL-6) and interleukin- 1ß (IL-1ß) in vivo. Transcriptomic data analysis showed there were 10 key driver analysis (KDA) genes with the strongest correlation which JTW regulated in depression mice. Molecular docking analysis displayed bioactive compound Magnoflorine had the strongest binding force to the key gene colony-stimulating factor 1 receptor (CSF1R), which is the signaling microglia dependent upon for their survival. Meanwhile, CSF1R staining showed it was consistent with inflammatory activation of microglia. Our vitro experiment also showed JTW and CSF1R inhibitor significantly reduced lipopolysaccharide (LPS)/interferon-gamma (IFNÉ£)-induced inflammatory activation response in macrophage cells. CONCLUSIONS: Our study suggests that JTW might ameliorate CORT-induced neuronal damage in depression mice by inhibiting CSF1R mediated microglia activation and pro-inflammatory response.
Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Inflamação/tratamento farmacológico , Animais , Animais não Endogâmicos , Comportamento Animal/efeitos dos fármacos , Corticosterona/toxicidade , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Simulação de Acoplamento Molecular , Células RAW 264.7RESUMO
Maternally derived hormones induce variation in offspring phenotype, with consequences that can carry over into post-natal life and even into adulthood. In birds, maternal egg corticosterone (CORT) is known to exert contrasting effects on offspring morphology, physiology and behaviour after hatching. However, information on the effects of CORT exposure on pre-hatching embryonic development is limited. We experimentally increased yolk CORT levels in yellow-legged gull (Larus michahellis) eggs, and assessed the effects on embryo pre-hatching development and oxidative status of brain and liver. CORT-supplemented embryos reached a larger skeletal size and liver mass compared with controls. Embryos from CORT-injected last-laid eggs showed decreased activity of the hepatic antioxidant enzymes superoxide dismutase and catalase, while intermediate-laid eggs showed increased levels of lipid peroxidation. However, elevated yolk CORT did not affect oxidative stress endpoints in the brain. Our results indicate that elevated yolk CORT levels affect prenatal embryo development by promoting skeletal growth, and induce laying sequence- and organ-specific oxidative imbalance, with potential adverse consequences during postnatal life, especially for late-hatched offspring.
Assuntos
Charadriiformes , Animais , Antioxidantes/metabolismo , Charadriiformes/metabolismo , Corticosterona/metabolismo , Corticosterona/toxicidade , Gema de Ovo/metabolismo , Estresse OxidativoRESUMO
The effect of stress on male fertility is a widespread public health issue, but less is known about the related signaling pathway. To investigate this, we established a hypercortisolism mouse model by supplementing the drinking water with corticosterone for four weeks. In the hypercortisolism mice, the serum corticosterone was much higher than in the control, and serum testosterone was significantly decreased. Moreover, corticosterone treatment induced decrease of sperm counts and increase of teratozoospermia. Increased numbers of multinucleated giant cells and apoptotic germ cells as well as downregulated meiotic markers suggested that corticosterone induced impaired spermatogenesis. Further, upregulation of macrophage-specific marker antigen F4/80 as well as inflammation-related genes suggested that corticosterone induced inflammation in the testis. Lactate content was found to be decreased in the testis and Sertoli cells after corticosterone treatment, and lactate metabolism-related genes were downregulated. In vitro phagocytosis assays showed that the phagocytic activity in corticosterone-treated Sertoli cells was downregulated and accompanied by decreased mitochondrial membrane potential, while pyruvate dehydrogenase kinase-4 inhibitor supplementation restored this process. Taken together, our results demonstrated that dysfunctional phagocytosis capacity and lactate metabolism in Sertoli cells participates in corticosterone-induced impairment of spermatogenesis.
Assuntos
Glucocorticoides/toxicidade , Células de Sertoli/fisiologia , Espermatogênese/efeitos dos fármacos , Animais , Proteínas de Ligação ao Cálcio/análise , Corticosterona/toxicidade , Síndrome de Cushing/sangue , Síndrome de Cushing/induzido quimicamente , Síndrome de Cushing/fisiopatologia , Ácido Dicloroacético/farmacologia , Hormônio Foliculoestimulante/sangue , Ácido Láctico/metabolismo , Hormônio Luteinizante/sangue , Masculino , Meiose/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Orquite/induzido quimicamente , Orquite/metabolismo , Fagocitose/efeitos dos fármacos , Piruvato Desidrogenase Quinase de Transferência de Acetil/antagonistas & inibidores , Receptores Acoplados a Proteínas G/análise , Células de Sertoli/metabolismo , Contagem de Espermatozoides , Espermatozoides/patologia , Testículo/metabolismo , Testosterona/sangueRESUMO
This study aims to investigate the effect of hesperidin on CORT-induced apoptosis and oxidative stress of mouse hippocampal nerve cells by up-regulating miR-146a-5p and related mechanism. Hesperidin was applied to CORT-induced HT-22 cells, or HT-22 cells whose expression of mir-146a-5p was up-regulated or down-regulated by CORT. The apoptosis rate was detected by flow cytometry. Expression of Cleaved-caspase-3 protein in cells was detected by Western blot. The levels of MDA, SOD and CAT in the cells were detected by enzyme-linked immunosorbent assay, and the expression of miR-146a-5p was detected by RT-qPCR. The application of hesperidin or up-regulation of miR-146a-5p can reduce the CORT-induced apoptosis rate of HT-22 cells, Cleaved caspase-3 protein expression and MAD content (p<0.05), and increase the activity of SOD and CAT and the expression of miR-146a-5p (p<0.05). In contrast, down-regulation ofmiR-146a-5p can increase the CORT-induced apoptosis rate of HT-22 cells, Cleaved caspase-3 protein expression and MAD content (p<0.05), and decrease the activity of SOD and CAT and the expression of miR-146a-5p (p<0.05). Down-regulation of miR-146a-5p expression can reverse the effects of hesperidin on CORT-induced HT-22 cell apoptosis and oxidative stress. Hesperidin may protect cells from being damaged by up-regulating miR-146a-5p to reduce CORT-induced HT-22 cell apoptosis and oxidative stress.
Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Corticosterona/toxicidade , Hesperidina/farmacologia , Hipocampo/efeitos dos fármacos , MicroRNAs/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Linhagem Celular , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , MicroRNAs/genética , Neurônios/metabolismo , Neurônios/patologia , Transdução de Sinais , Regulação para CimaRESUMO
Activated astrocytes play a key role in diabetic neuropathic pain and depression. We aimed to assess the protective effects of dihydromyricetin (DHM) on primary hippocampal astrocytes cultured with high glucose (HG), substance P (SP), and corticosterone (CORT). Culturing with HG + SP + CORT resulted in damage to primary hippocampal astrocytes, which simulates the clinical damage caused by comorbidity of diabetic neuropathic pain and depression. Western blot, qPCR, and immunofluorescence analyses revealed that HG + SP + CORT increased P2X7 receptor expression in primary hippocampal astrocytes, which was reversed by DHM treatment. Further, HG + SP + CORT elevated TNF-α, IL-1ß, free Ca2+, and ERK1/2 phosphorylation levels, which was inhibited by DHM or P2X7 shRNA treatment. Moreover, DHM significantly reduced the P2X7 agonist-activated currents in HEK293 cells transfected with the P2X7 receptor. These findings suggest that DHM can protect primary hippocampal astrocytes cultured with HG + SP + CORT from P2X7 receptor-mediated damage. Culturing cells with HG + SP + CORT might be a viable cell model for cellular injury exploration of diabetic comorbid pain and depression.
Assuntos
Astrócitos/efeitos dos fármacos , Depressão , Neuropatias Diabéticas , Flavonóis/farmacologia , Animais , Astrócitos/metabolismo , Células Cultivadas , Corticosterona/toxicidade , Modelos Animais de Doenças , Glucose/toxicidade , Células HEK293 , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Camundongos , Neuralgia/metabolismo , Ratos , Ratos Sprague-Dawley , Substância P/toxicidadeRESUMO
Liquiritin, a flavone derived from the medicine food homology plant liquorice, possesses neuroprotective. However, the neuroprotective mechanism is not clear. In this study, metabolomics based LC-MS was performed to discover the metabolite changes in PC12 cells treated with corticosterone-induced neurotoxicity after liquiritin treatment. A total of 30 metabolites were identified as differential metabolites. Among them, 11 metabolites were regulated by liquiritin, and involved in the D-glutamine and D-glutamate metabolism, and glutathione metabolism, etc. Based on the results of metabolomics, three cell signaling pathways related to these metabolic pathways were verified. The results showed that the ERK1/2-NF-κB pathway related to the D-glutamine and D-glutamate metabolism was attenuated by liquiritin via down-regulation phospho-ERK1/2, phospho-IκBα, phospho-NF-κB protein expression levels. Furthermore, the Nrf2-Keap1 pathway related to glutathione metabolism was activated by liquiritin via up-regulation Nrf2, Keap1, HO-1, NQO1 protein expression levels, and increased SOD, CAT, GSH-PX enzyme activity, thus exerting antioxidant activity. Additionally, liquiritin inhibited the mitochondrial apoptosis by decreasing the Ca2+ concentration, improving MMP, up-regulating Bcl-2, and down-regulating Bax, cytochrome C, cleaved-Caspase-3 expression levels. These results suggest that the neuroprotective mechanisms of liquiritin are connected to the regulation of metabolic disorders, activation Nrf2/Keap1 pathway, attenuation ERK1/2/NF-κB pathway, and inhibition mitochondrial apoptosis pathway.
Assuntos
Apoptose/efeitos dos fármacos , Corticosterona/toxicidade , Flavanonas/farmacologia , Glucosídeos/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Doenças Metabólicas/prevenção & controle , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Animais , Flavanonas/isolamento & purificação , Glucosídeos/isolamento & purificação , Glycyrrhiza/química , Células PC12 , RatosRESUMO
RATIONALE: Currently available PDE2 inhibitors have poor brain penetration that limits their therapeutic utility in the treatment of depression. Hcyb1 is a novel selective PDE2 inhibitor that was introduced more lipophilic groups with polar functionality to the scaffold pyrazolopyrimidinone to improve the blood-brain barrier (BBB) penetration. Our previous study suggested that Hcyb1 increased the neuronal cell viability and exhibited antidepressant-like effects, which were parallel to the currently available PDE2 inhibitor Bay 60-7550. OBJECTIVES: The present study investigated whether Hcyb1 protected HT-22 cells against corticosterone-induced neurotoxicity and produced antidepressant-like effects in behavioral tests in stressed mice. METHODS: The neuroprotective effects of Hcyb1 against corticosterone-induced cell lesion were examined by cell viability (MTS) assay. The enzyme-linked immunosorbent assay (ELISA) and immunoblot analysis were used to determine the levels of cAMP or cGMP and expression of pCREB or BDNF, respectively, in the corticosterone-treated HT-22 cells. The antidepressant-like effects of Hcyb1 were determined in the tail suspension and novelty suppressed feeding tests in stressed mice. RESULTS: In the cell-based assay, Hcyb1 significantly increased cell viability of HT-22 cells against corticosterone-induced neurotoxicity in a time- and dose-dependent manner. Hcyb1 also rescued corticosterone-induced decreases in both cGMP and cAMP levels, pCREB/CREB and BDNF expression. These protective effects of Hcyb1 were prevented by pretreatment with either the PKA inhibitor H89 or the PKG inhibitor KT5823. Moreover, Hcyb1 reversed acute stress-induced increases in immobility time and the latency to feed in the tail suspension and novelty suppressed feeding tests, respectively, which were prevented by pretreatment with H89 or KT5823. CONCLUSION: These findings provide evidence that the neuroprotective effects of Hcyb1 are mediated by PDE2-dependent cAMP/cGMP signaling.
Assuntos
Antidepressivos/uso terapêutico , Corticosterona/toxicidade , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Depressão/tratamento farmacológico , Síndromes Neurotóxicas/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Depressão/metabolismo , Depressão/psicologia , Elevação dos Membros Posteriores/efeitos adversos , Elevação dos Membros Posteriores/psicologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/psicologia , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologiaRESUMO
Glucocorticoids (GCs), stress-induced steroid hormones, are released by adrenal cortex and essential for stress adaptation. Recently, there has been renewed interest in the relationship between GCs and pregnancy following the discovery that glucocorticoid receptor is necessary for implantation. It has been widely recognized that stress is detrimental to pregnancy. However, effects of stress-induced GC exposure on uterine receptivity and decidualization are still poorly understood. This study aims to explore the effects of GCs exposure on uterine receptivity, decidualization, and their underlying mechanisms in mice. Single prolonged stress (SPS) and corticosterone (Cort) injection models were used to analyze effects of GC exposure on early pregnancy, respectively. SPS or Cort injection inhibits embryo implantation by interfering Lif signaling and stimulating the uterine deposition of collagen types I, III, and IV on day 4 of pregnancy. Uterine decidualization is also attenuated by SPS or Cort injection through suppressing Cox-2 expression. Cort-induced collagen disorder also suppresses decidualization through regulating mesenchymal-epithelial transition. Our data should shed lights for a better understanding for the effects of GCs on embryo implantation for clinical research.
Assuntos
Anti-Inflamatórios/toxicidade , Corticosterona/toxicidade , Decídua/patologia , Implantação do Embrião/efeitos dos fármacos , Estresse Fisiológico , Útero/patologia , Animais , Decídua/efeitos dos fármacos , Feminino , Masculino , Camundongos , Gravidez , Útero/efeitos dos fármacosRESUMO
Ketamine has been reported to exert a prophylactic effect against stress-induced depressive-like behavior by modulating the guanosine-based purinergic system. However, the molecular pathways underlying its prophylactic effect and whether guanosine also elicits a similar effect remain to be determined. Here, we investigated the prophylactic effect of ketamine and guanosine against corticosterone (CORT - 20â¯mg/kg, p.o.)-induced depressive-like behavior in mice. Furthermore, we characterized if the prophylactic response may be associated with mTORC1-driven signaling in the hippocampus and prefrontal cortex. A single administration of ketamine (5â¯mg/kg, i.p.), but not guanosine (1 or 5â¯mg/kg, p.o.), given 1â¯week before the pharmacological stress prevented CORT-induced depressive-like behavior in the tail suspension test (TST) and splash test (SPT). Fluoxetine treatment for 3â¯weeks did not prevent CORT-induced behavioral effects. A single administration of subthreshold doses of ketamine (1â¯mg/kg, i.p.) plus guanosine (5â¯mg/kg, p.o.) partially prevented the CORT-induced depressive-like behavior in the SPT. Additionally, CORT reduced Akt (Ser473) and GSK-3ß (Ser9) phosphorylation and PSD-95, GluA1, and synapsin immunocontent in the hippocampus, but not in the prefrontal cortex. No alterations on mTORC1/p70S6K immunocontent were found in both regions in any experimental group. CORT-induced reductions on PSD-95, GluA1, and synapsin immunocontent were prevented only by ketamine treatment. Collectively, these findings suggest that ketamine, but not guanosine, exerts a prophylactic effect against depressive-like behavior, an effect associated with the stimulation of long-lasting pro-synaptogenic signaling in the hippocampus.
Assuntos
Corticosterona/toxicidade , Depressão/prevenção & controle , Guanosina/administração & dosagem , Ketamina/administração & dosagem , Profilaxia Pré-Exposição/métodos , Sinapses/fisiologia , Animais , Antidepressivos/administração & dosagem , Depressão/induzido quimicamente , Depressão/psicologia , Elevação dos Membros Posteriores/efeitos adversos , Elevação dos Membros Posteriores/psicologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Sinapses/efeitos dos fármacosRESUMO
This study investigated the protective effects of maca ethanol extract (EEM) and N-(3-methozybenzyl)-(9Z,12Z,15Z)-octadecatrienamide (M 18:3) on corticosterone (CORT)-induced testicular toxicity. Male Wistar rats were divided into 5 groups. Except for the control group, CORT (40 mg per kg·bw) was injected subcutaneously for 21 consecutive days to induce testicular toxicity. 1 h before CORT injection, the rats were treated with EEM (400 mg per kg·bw) and M 18:3 (5 mg per kg·bw, 25 mg per kg·bw) by gavage, except for the control group and model group. Epididymal sperm and biochemical, and histological parameters were evaluated for the protective effects of the drugs. EEM (400 mg per kg·bw) and M 18:3 (5 mg per kg·bw, 25 mg per kg·bw) increased the sperm concentration and sperm motility, decreased the production of abnormal sperms, and increased the number of spermatogonia and primary spermatocytes in the seminiferous tubules of CORT-induced rats. Moreover, EEM and M 18:3 decreased the MDA levels and the positive expression rates of TUNEL, whereas they increased the activities of SOD, CAT, GSH-Px, and GST, and the contents of GSH in the testicles of CORT-induced rats. Furthermore, EEM and M 18:3 alleviated CORT-induced reduction in the positive expression rates of PCNA and Ki67 in the testicles of rats. Besides, EEM and M 18:3 reduced the expression levels of Keap-1 and increased the expression levels of Nrf2, HO-1, γ-GCS, and NQO1 in the testicles of CORT-induced rats. In summary, the protective effects of EEM and M 18:3 may be attributed to their anti-oxidative and anti-apoptotic properties.
Assuntos
Corticosterona/toxicidade , Lepidium/química , Extratos Vegetais/farmacologia , Testículo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Antígeno Ki-67/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Extratos Vegetais/química , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Wistar , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Túbulos Seminíferos/efeitos dos fármacos , Túbulos Seminíferos/patologia , Contagem de Espermatozoides , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatozoides/anormalidades , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Testículo/metabolismoRESUMO
Recent studies have showed that ketamine is a rapid and efficient antidepressant, but the mechanism of its antidepressant effect is not fully clear. It is still lack of the research investigating the relation between depressive-like behaviors and neuronal activities in specific brain area after administration of ketamine in vivo. Medial prefrontal cortex (mPFC) involved in the pathogenesis of depression. As a result of effective assessments after behavioral test, most studies lack of direct evidence of the relation between efficacy and the activity of specific brain area. Therefore, we used fiber photometry to explore the alteration of Ca2+ transient in the prelimbic (PrL) area of mPFC during behavioral tests in freely moving mice. Our results showed that the chronic corticosterone (CORT) protocol induced depressive-like behaviors. Administration of ketamine reversed these effects. The activation of Ca2+ transients was associated with some behaviors during behavioral tests. Struggling, rearing and exploring evoked strong Ca2+ transients, but moving and grooming did not. The Ca2+ transients amplitude reductions of struggling, rearing and exploring induced by CORT were reversed by ketamine. The results indicated that ketamine ameliorated depressive-like behaviors via mediating neural activation in PrL.
Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Corticosterona/toxicidade , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Ketamina/uso terapêutico , Córtex Pré-Frontal/efeitos dos fármacos , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Sinalização do Cálcio/fisiologia , Corticosterona/administração & dosagem , Depressão/metabolismo , Feminino , Ketamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismoRESUMO
Augmentative treatment is considered the best second-option when a first-choice drug has partial limitations, particularly by allowing antidepressant dose reduction. Considering that ketamine has significant knock-on effects, this study investigated the effects of a single coadministration with subthreshold doses of ketamine plus guanosine in a corticosterone (CORT)-induced animal model of depression and the role of anti-inflammatory and antioxidant pathways. CORT administration (20 mg/kg, p.o. for 21 days) increased the immobility time in the tail suspension test (TST) and the grooming latency in the splash test (SPT), as well as reduced the total time of grooming in the SPT. These behavioral alterations were accompanied by impaired hippocampal slices viability, elevated immunocontent of nuclear factor-kappa B (NF-κB) and indoleamine-2,3-dioxygenase 1 (IDO-1), and reduced immunocontent of glucocorticoids receptor (GR), glutamate transporter (GLT-1), nuclear factor-erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in the hippocampus. CORT also decreased the thioredoxin reductase activity in the hippocampus, while reduced the glutathione reductase activity and non-protein thiols levels in both hippocampus and prefrontal cortex. In addition, elevated content of malondialdehyde and protein carbonyl was also observed in the hippocampus and prefrontal cortex of CORT-treated mice. Of note, a single administration of ketamine (0.1 mg/kg, i.p.) plus guanosine (0.01 mg/kg, p.o.) attenuated the depressive-like behavior and hippocampal slices impairments induced by CORT. The behavioral response obtained by the combined administration of these drugs was paralleled by the reestablishment of the CORT-induced molecular alterations on hippocampal GR, NF-κB, IDO-1, and GLT-1 immunocontent. Moreover, CORT-induced alterations on the antioxidant enzyme activity and oxidative stress markers were partially restored by ketamine plus guanosine treatment. Taken together, these findings suggest that guanosine might potentiate the effects of ketamine on inflammatory and oxidative markers that are elevated in depression.
Assuntos
Antidepressivos/administração & dosagem , Guanosina/administração & dosagem , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Ketamina/administração & dosagem , NF-kappa B/antagonistas & inibidores , Receptores de Glucocorticoides/antagonistas & inibidores , Animais , Corticosterona/toxicidade , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Depressão/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Camundongos , NF-kappa B/metabolismo , Receptores de Glucocorticoides/metabolismoRESUMO
Context: In folk medicine, erxian decoction (EXD) is used to treat perimenopausal syndrome in women. It is also used clinically to treat depression, but the mechanism remains unknown.Objectives: To investigate the neuroprotective effect of EXD, and its antidepressant potential.Materials and methods: ICR mice were treated with EXD (0.5, 1.5 and 4.5 g/kg i.g.) and fluoxetine (6.0 mg/kg i.g.) for 10 days. On day 10 of the treatment, depression-like behaviour was induced by reserpine (2.5 mg/kg injected i.p.), and after 24 h of reserpine administration, it was assessed using the tail suspension and forced swimming tests. MTT assay, lactate dehydrogenase test, flow cytometry analysis, Hoechst staining and western blotting were used to assess the apoptosis of PC12 cells. Apoptosis proteins and neurotransmitter were tested in vitro and in vivo, respectively.Results: MTT assay results showed corticosterone prevented cell growth, but EXD at concentrations of 100, 200 and 400 µg/mL restored cell viability (EC50: 204.016 µg/mL). EXD decreased lactate dehydrogenase leakage from 63.48 to 43.60 U/L, and upregulated expression of Bcl-2 while the expression of Bax, caspase-3 and caspase-8 were decreased in vivo and in vitro. Moreover, EXD improved depression-like behaviour in mice, and 4.5 g/kg EXD treatment increased the secretion of serotonin, dopamine and norepinephrine by 67.44, 28.12 and 42.12 pg/mg, respectively, in hypothalamus compared to that of reserpine group.Discussion and conclusions: EXD demonstrated neuroprotective effects and improved depression-like behaviour in mice. Further research should be focussed on the mechanism of the active components in EXD.
Assuntos
Sobrevivência Celular/efeitos dos fármacos , Corticosterona/toxicidade , Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Animais , Sobrevivência Celular/fisiologia , Depressão/psicologia , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Masculino , Medicina Tradicional Chinesa/métodos , Camundongos , Camundongos Endogâmicos ICR , Células PC12 , RatosRESUMO
Chronic treatment with agmatine, similarly to fluoxetine, may cause antidepressant-like effects mediated, at least in part, by the modulation of hippocampal plasticity. However, the ability of chronic treatment with agmatine to cause antidepressant-like effects associated with the modulation of mammalian target of rapamycin (mTOR) signaling pathway and protection against neuronal death remains to be established. In this study, we investigated the effects of agmatine (0.1 mg/kg, p.o.) and the conventional antidepressant fluoxetine (10 mg/kg, p.o.) treatment on the levels of phosphorylated mTOR (p-mTOR), neuronal death, and overall volume in the hippocampal dentate gyrus (DG) of mice exposed to chronic corticosterone (20 mg/kg, p.o.) treatment for 21 days, a model of stress and depressive-like behavior. Chronic corticosterone treatment increased cell death in the sub-granular zone (SGZ) of the DG, as assessed by Fluoro-Jade B labeling. Agmatine, similarly to fluoxetine, was capable of reversing this alteration in the entire DG, an effect more evident in the ventral portion of the hippocampus. Additionally, reduced phosphorylation of mTOR (Ser2448), a pro-survival protein that is active when phosphorylated at Ser2448, was observed in the whole hippocampal DG in corticosterone-treated mice, an effect not observed in agmatine or fluoxetine-treated mice. Chronic exposure to corticosterone caused a significant reduction in overall hippocampal volume, although no alterations were observed between the groups with regards to DG volume. Altogether, the results indicate that agmatine, similar to fluoxetine, was able to counteract corticosterone-induced impairment on mTOR signaling and cell death in hippocampal DG.
Assuntos
Agmatina/farmacologia , Anti-Inflamatórios/toxicidade , Corticosterona/toxicidade , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Serina-Treonina Quinases TOR/efeitos dos fármacos , Animais , Morte Celular/efeitos dos fármacos , Giro Denteado/citologia , Giro Denteado/efeitos dos fármacos , Fluoxetina/farmacologia , Hipocampo/metabolismo , Camundongos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND: Maternal obesity as a result of high levels of saturated fat (HFD) consumption leads to significant negative health outcomes in both mother and exposed offspring. Offspring exposed to maternal HFD show sex-specific alterations in metabolic, behavioral, and endocrine function, as well as increased levels of basal neuroinflammation that persists into adulthood. There is evidence that psychosocial stress or exogenous administration of corticosterone (CORT) potentiate inflammatory gene expression; however, the response to acute CORT or immune challenge in adult offspring exposed to maternal HFD during perinatal life is unknown. We hypothesize that adult rat offspring exposed to maternal HFD would show enhanced pro-inflammatory gene expression in response to acute administration of CORT and lipopolysaccharide (LPS) compared to control animals, as a result of elevated basal pro-inflammatory gene expression. To test this, we examined the effects of acute CORT and/or LPS exposure on pro and anti-inflammatory neural gene expression in adult offspring (male and female) with perinatal exposure to a HFD or a control house-chow diet (CHD). METHODS: Rat dams consumed HFD or CHD for four weeks prior to mating, during gestation, and throughout lactation. All male and female offspring were weaned on to CHD. In adulthood, offspring were 'challenged' with administration of exogenous CORT and/or LPS, and quantitative PCR was used to measure transcript abundance of glucocorticoid receptors and downstream inflammatory markers in the amygdala, hippocampus, and prefrontal cortex. RESULTS: In response to CORT alone, male HFD offspring showed increased levels of anti-inflammatory transcripts, whereas in response to LPS alone, female HFD offspring showed increased levels of pro-inflammatory transcripts. In addition, male HFD offspring showed greater pro-inflammatory gene expression and female HFD offspring exhibited increased anti-inflammatory gene expression in response to simultaneous CORT and LPS administration. CONCLUSIONS: These findings suggest that exposure to maternal HFD leads to sex-specific changes that may alter inflammatory responses in the brain, possibly as an adaptive response to basal neuroinflammation.
Assuntos
Corticosterona/toxicidade , Dieta Hiperlipídica/efeitos adversos , Glucocorticoides/metabolismo , Mediadores da Inflamação/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Caracteres Sexuais , Animais , Feminino , Lipopolissacarídeos/toxicidade , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Long-Evans , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
Maca has been traditionally used to enhance sexual behavior and fertility. Recently, maca's neuroprotective effects have been reported. The purpose of this study was to investigate whether the ethanol extract of maca (EEM) (100 mg/kg/bw, 200 mg/kg/bw, 400 mg/kg/bw, p.o.) exerted neuroprotective effects in corticosterone (CORT)-induced (40 mg/kg/bw, s.c.) rats, to determine the neuroprotective effects of EEM (12.5, 25, 50 µg/ml) and macamides in H2O2-induced (50 µM) PC12 cells. The acute toxicity (2000 mg/kg/bw, p.o.) and subacute toxicity (200 mg/kg/bw, 500 mg/kg/bw, 1000 mg/kg/bw, p.o.) of EEM were evaluated by mouse models. EEM reversed CORT-induced abnormal behaviors, reduced the contents of TNF-α, IL-6 in hippocampi, and increased the positive cells of doublecortin (DCX), bromodeoxyuridine (BrdU) and DCX + BrdU in the hippocampus of rats. Moreover, EEM and 4 macamides remarkably increased the cell viability in H2O2-induced PC12 cells. EEM promoted the phosphorylation of IκBα and p65, suppressed the NF-κB activation, and inhibited the levels of pro-inflammatory cytokines such as TNF-α, IL-6 and their mRNA levels in H2O2-induced PC12 cells. In conclusion, EEM could exert neuroprotective effects in CORT-induced rats and in H2O2-induced PC12 cells. Moreover, EEM did not present relevant toxicity after exposure to single and repeated doses.