RESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and memory loss. Imipramine, a tricyclic antidepressant, has potent anti-inflammatory and antioxidant properties in the central nervous system. The aim of this study was to investigate the neuroprotective effects of imipramine on streptozotocin (STZ)-induced memory impairment. Male Wistar rats received an intracerebroventricular injection of STZ (3 mg/kg, 3 µl/ventricle) using the stereotaxic apparatus. The Morris water maze and passive avoidance tests were used to evaluate cognitive functions. 24 h after the STZ injection, imipramine was administered intraperitoneally at doses of 10 or 20 mg/kg for 14 consecutive days. The mRNA and protein levels of neurotrophic factors (BDNF and GDNF) and pro-inflammatory cytokines (IL-6, IL-1ß, and TNF-α) were measured in the hippocampus using real-time PCR and ELISA techniques, respectively. In addition, real-time PCR was used to evaluate the mRNA levels of markers associated with neurogenesis (Nestin, DCX, and Ki67) and mitochondrial biogenesis (PGC-1α, NRF-1, and TFAM). The results showed that imipramine, especially at a dose of 20 mg/kg, effectively improved STZ-induced memory impairment. This improvement was associated with an increase in neurogenesis and neurotrophic factors and a decrease in neuroinflammation and mitochondrial biogenesis dysfunction. Based on these results, imipramine appears to be a promising therapeutic option for improving cognitive functions in neurodegenerative diseases such as AD.
Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Hipocampo , Imipramina , Neurogênese , Biogênese de Organelas , Ratos Wistar , Estreptozocina , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Masculino , Neurogênese/efeitos dos fármacos , Imipramina/farmacologia , Ratos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Proteína Duplacortina , Doenças Neuroinflamatórias/tratamento farmacológico , Memória/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Antidepressivos Tricíclicos/farmacologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Citocinas/metabolismoRESUMO
OBJECTIVE: Ganoderic Acid A (GAA), a primary bioactive component in Ganoderma, has demonstrated ameliorative effects on depressive-like behaviors in a Chronic Social Defeat Stress (CSDS) mouse model. This study aims to elucidate the underlying molecular mechanisms through proteomic analysis. METHODS: C57BL/6 J mice were allocated into control (CON), chronic social defeat stress (CSDS), GAA, and imipramine (IMI) groups. Post-depression induction via CSDS, the GAA and IMI groups received respective treatments of GAA (2.5 mg/kg) and imipramine (10 mg/kg) for five days. Behavioral assessments utilized standardized tests. Proteins from the prefrontal cortex were analyzed using LC-MS, with further examination via bioinformatics and PRM for differential expression. Western blot analysis confirmed protein expression levels. RESULTS: Chronic social defeat stress (CSDS) induced depressive-like behaviors in mice, which were significantly alleviated by GAA treatment, comparably to imipramine (IMI). Proteomic analysis identified distinct proteins in control (305), GAA-treated (949), and IMI-treated (289) groups. Enrichment in mitochondrial and synaptic proteins was evident from GO and PPI analyses. PRM analysis revealed significant expression changes in proteins crucial for mitochondrial and synaptic functions (namely, Naa30, Bnip1, Tubgcp4, Atxn3, Carmil1, Nup37, Apoh, Mrpl42, Tprkb, Acbd5, Dcx, Erbb4, Ppp1r2, Fam3c, Rnf112, and Cep41). Western blot validation in the prefrontal cortex showed increased levels of Mrpl42, Dcx, Fam3c, Ppp1r2, Rnf112, and Naa30 following GAA treatment. CONCLUSION: GAA exhibits potential antidepressant properties, with its action potentially tied to the modulation of synaptic functions and mitochondrial activities.
Assuntos
Comportamento Animal , Depressão , Modelos Animais de Doenças , Lanosterol , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal , Proteômica , Derrota Social , Estresse Psicológico , Animais , Camundongos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Masculino , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Lanosterol/análogos & derivados , Lanosterol/farmacologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Imipramina/farmacologia , Proteína Duplacortina , Ácidos HeptanoicosRESUMO
Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is linked to the pathophysiology of depression. Although exogenous adrenocorticotropic hormone (ACTH) is associated with a depressive-like phenotype in rodents, comprehensive neurobehavioral and mechanistic evidence to support these findings are limited. Sprague-Dawley rats (male, n = 30; female, n = 10) were randomly assigned to the control (male, n = 10) or ACTH (male, n = 20; female n = 10) groups that received saline (0.1 ml, sc.) or ACTH (100 µg/day, sc.), respectively, for two weeks. Thereafter, rats in the ACTH group were subdivided to receive ACTH plus saline (ACTH_S; male, n = 10; female, n = 5; 0.2 ml, ip.) or ACTH plus imipramine (ACTH_I; male, n = 10; female, n = 5;10 mg/kg, ip.) for a further four weeks. Neurobehavioral changes were assessed using the forced swim test (FST), the sucrose preference test (SPT), and the open field test (OFT). Following termination, the brain regional mRNA expression of BDNF and CREB was determined using RT-PCR. After two-weeks, ACTH administration significantly increased immobility in the FST (p = 0.03), decreased interaction with the center of the OFT (p < 0.01), and increased sucrose consumption (p = 0.03) in male, but not female rats. ACTH administration significantly increased the expression of BDNF in the hippocampus and CREB in all brain regions in males (p < 0.05), but not in female rats. Imipramine treatment did not ameliorate these ACTH-induced neurobehavioral or molecular changes. In conclusion, ACTH administration resulted in a sex-specific onset of depressive-like symptoms and changes in brain regional expression of neurotrophic factors. These results suggest sex-specific mechanisms underlying the development of depressive-like behavior in a model of ACTH-induced HPA axis dysregulation.
Assuntos
Hormônio Adrenocorticotrópico , Fator Neurotrófico Derivado do Encéfalo , Sistema Hipotálamo-Hipofisário , Imipramina , Sistema Hipófise-Suprarrenal , Animais , Feminino , Masculino , Ratos , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Imipramina/farmacologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
Persistence is the propensity to maintain goal-directed actions despite adversities. While this temperamental trait is crucial to mitigate depression risk, its neurobiological foundations remain elusive. Developing behavioral tasks to capture persistence in animal models is crucial for understanding its molecular underpinnings. Here, we introduce the Sinking Platform Test (SPT), a novel high-throughput paradigm to measure persistence. Mice were trained to exit a water-filled tank by ascending onto a platform above water level. Throughout the training, mice were also occasionally exposed to "failure trials," during which an operator would submerge a platform right after the mouse climbed onto it, requiring the mouse to reach and ascend a newly introduced platform. Following training, mice were subjected to a 5-min test exclusively consisting of failure trials. Male and female mice exhibited comparable persistence, measured by the number of climbed platforms during the test. Furthermore, this index was increased by chronic administration of fluoxetine or imipramine; conversely, it was reduced by acute and chronic haloperidol. Notably, six weeks of social isolation reduced SPT performance, and this effect was rescued by imipramine treatment over the last two weeks. A 4-week regimen of voluntary wheel running also improved persistence in socially isolated mice. Finally, comparing transcriptomic profiles of the prefrontal cortex of mice with high and low SPT performance revealed significant enrichment of immediate-early genes known to shape susceptibility for chronic stress. These findings highlight the potential of SPT as a promising method to uncover the biological mechanisms of persistence and evaluate novel interventions to enhance this response.
Assuntos
Fluoxetina , Haloperidol , Camundongos Endogâmicos C57BL , Isolamento Social , Animais , Masculino , Camundongos , Feminino , Fluoxetina/farmacologia , Haloperidol/farmacologia , Isolamento Social/psicologia , Imipramina/farmacologia , Modelos Animais de Doenças , Comportamento Animal/fisiologia , Comportamento Animal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologiaRESUMO
OBJECTIVES: This study sought to identify pathways affected by rat cortical RNA that were changed after treatment with fluoxetine or imipramine. METHODS: We measured levels of cortical RNA in male rats using GeneChip® Rat Exon 1.0 ST Array after treatment with vehicle (0.9% NaCl), fluoxetine (10 mg/kg/day) or imipramine (20 mg/kg/day) for 28 days. Levels of coding and non-coding RNA in vehicle treated rats were compared to those in treated rats using ANOVA in JMP Genomics 13 and the Panther Gene Ontology Classification System was used to identify pathways involving the changed RNAs. RESULTS: 18,876 transcripts were detected; there were highly correlated changes in 1010 levels of RNA after both drug treatments that would principally affect the metabolism of polyamines, mRNA splicing, regulation of RAS by GAPs, neddylation and GPCR ligand binding. Using our previously published data, we compared changes in transcripts after treatment with antipsychotic and mood stabilising drugs. CONCLUSIONS: Our study shows there are common, correlated, changes in coding and non-coding RNA in the rat cortex after treatment with fluoxetine or imipramine; we propose the pathways affected by these changes are involved in the therapeutic mechanisms of action of antidepressant drugs.
Assuntos
Fluoxetina , Imipramina , Ratos , Masculino , Animais , Fluoxetina/farmacologia , Imipramina/farmacologia , Ligantes , Poliaminas , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G , Antidepressivos/farmacologia , Expressão Gênica , RNA , RNA Mensageiro , RNA não TraduzidoRESUMO
N-methyl-D-aspartic acid receptors (NMDARs) are the most studied receptors in mammalian brains. Their role in depression, cognition, schizophrenia, learning and memorization, Alzheimer's disease, and more is well documented. In the search for new drug candidates in depression, intensive studies have been conducted. Compounds that act by influencing NMDARs have been particularly intensively investigated following the success of ketamine in clinics. Unfortunately, the side effects associated with ketamine do not allow it to be useful in all cases. Therefore, it is important to learn about new unknown mechanisms related to NMDAR activation and study the impact of changes in the excitatory synapse environment on this receptor. Both direct and intermediary influence on NMDARs via mGluRs and COX-2 are effective. Our prior studies showed that both mGluRs ligands and COX-2 inhibitors are potent in depression-like and cognitive studies through mutual interactions. The side effects associated with imipramine administration, e.g., memory impairment, were improved when inhibiting COX-2. Therefore, this study is a trial that involves searching for modifications in NMDARs in mouse brains after prolonged treatment with MTEP (mGluR5 antagonist), NS398 (COX-2 inhibitor), or imipramine (tricyclic antidepressant). The prefrontal cortex (PFC) and hippocampus (HC) were selected for PCR and Western blot analyses. Altered expression of Gin2a or Grin2b genes after treatment was found. The observed effects were more potent when COX-2 was inhibited. The finding described here may be vital when searching for new drugs acting via NMDARs without the side effects related to cognition.
Assuntos
Ketamina , Camundongos , Animais , Ciclo-Oxigenase 2/metabolismo , Ketamina/farmacologia , Imipramina/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Hipocampo , Mamíferos/metabolismoRESUMO
BACKGROUND: Bipolar disorder (BD) is a highly burdensome psychiatric disorder characterized by alternating states of mania and depression. A major challenge in the clinic is the switch from depression to mania, which is often observed in female BD patients during antidepressant treatment such as imipramine. However, the underlying neural basis is unclear. METHODS: To investigate the potential neuronal pathways, serotonin transporter knockout (SERT KO) rats, an experimental model of female BD patients, were subjected to a battery of behavioral tests under chronic treatment of the antidepressant imipramine. In addition, the expression of brain-derived neurotrophic factor (BDNF) and its downstream signaling was examined in the prefrontal cortex. RESULTS: Chronic exposure to imipramine reduced anxiety and sociability and problem-solving capacity, and increased thigmotaxis and day/night activity in all animals, but specifically in female SERT KO rats, compared to female wild-type (WT) rats. Further, we found an activation of BDNF-TrkB-Akt pathway signaling in the infralimbic, but not prelimbic, cortex after chronic imipramine treatment in SERT KO, but not WT, rats. LIMITATIONS: Repeated testing behaviors could potentially affect the results. Additionally, the imipramine induced changes in behavior and in the BDNF system were measured in separate animals. CONCLUSIONS: Our study indicates that female SERT KO rats, which mirror the female BD patients with the 5-HTTLPR s-allele, are at higher risk of a switch to mania-like behaviors under imipramine treatment. Activation of the BDNF-TrkB-Akt pathway in the infralimbic cortex might contribute to this phenotype, but causal evidence remains to be provided.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Imipramina , Humanos , Ratos , Feminino , Animais , Imipramina/farmacologia , Imipramina/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Mania/metabolismo , Depressão , Proteínas Proto-Oncogênicas c-akt/metabolismo , Antidepressivos/farmacologia , Hipocampo/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Litsea glaucescens K. (Lauraceae) is a small tree from the Mexican and Central American temperate forests, named as "Laurel". Its aromatic leaves are ordinarily consumed as condiments, but also are important in Mexican Traditional Medicine, and among the most important non wood forest products in this area. The leaves are currently used in a decoction for the relief of sadness by the Mazahua ethnic group. Interestingly, "Laurel" has a long history. It was named as "Ehecapahtli" (wind medicine) in pre-Columbian times and applied to heal maladies correlated to the Central Nervous System, among them depression, according to botanical texts written in the American Continent almost five centuries ago. AIM OF THE STUDY: Depression is the first cause of incapacity in the world, and society demands alternative treatments, including aromatherapy. We have previously demonstrated the antidepressant-like activity of L. glaucescens leaves' essential oil (LEO), as well as their monoterpenes linalool, and beta-pinene by intraperitoneal route in a mice behavioral model. Here we now examined if LEO and linalool exhibit this property and anxiolytic activity when administered to mice by inhalation. We also investigated if these effects occur by BDNF pathway activation in the brain. MATERIALS AND METHODS: The LEO was prepared by distillation with water steam and analyzed by gas chromatography-mass spectrometry (GC-MS). The monoterpenes linalool, eucalyptol and ß-pinene were identified and quantified. Antidepressant type properties were determined with the Forced Swim Test (FST) on mice previously exposed to LEO or linalool in an inhalation chamber. The spontaneous locomotor activity and the sedative effect were assessed with the Open Field Test (OFT), and the Exploratory Cylinder (EC), respectively. The anxiolytic properties were investigated with the Elevated Plus Maze Apparatus (EPM) and the Hole Board Test (HBT). All experiments were video documented. The mice were subjected to euthanasia, and the brain hippocampus and prefrontal cortex were dissected. RESULTS: The L. glaucescens essential oil (LEO) contains 31 compounds according to GC/MS, including eucalyptol, linalool and beta-pinene. The LEO has anxiolytic effect by inhalation in mice, as well as linalool, and ß-pinene, as indicated by OFT and EC tests. The LEO and imipramine have antidepressant like activity in mice as revealed by the FST; however, linalool and ketamine treatments didn't modify the time of immobility. The BDNF was increased in FST in mice treated with LEO in both areas of the brain as revealed by Western blot; but did not decrease the level of corticosterone in plasma. The OFT indicated that LEO and imipramine didn't reduce the spontaneous motor activity, while linalool and ketamine caused a significant decrease. CONCLUSION: Here we report by the first time that L. glaucescens leaves essential oil has anxiolytic effect by inhalation in mice, as well as linalool, and ß-pinene. This oil also maintains its antidepressant-like activity by this administration way, similarly to the previously determined intraperitoneally. Since inhalation is a common administration route for humans, our results suggest L. glaucescens essential oil deserve future investigation due to its potential application in aromatherapy.
Assuntos
Ansiolíticos , Ketamina , Lauraceae , Litsea , Óleos Voláteis , Humanos , Camundongos , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Óleos Voláteis/química , Fator Neurotrófico Derivado do Encéfalo , Imipramina/farmacologia , Eucaliptol/farmacologia , Ketamina/farmacologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antidepressivos/química , Monoterpenos/farmacologia , Comportamento AnimalRESUMO
Nephrotoxicity is a serious complication commonly encountered with gentamicin (GTM) treatment. Permeabilization of lysosomes with subsequent cytoplasmic release of GTM and cathepsins is considered a crucial issue in progression of GTM toxicity. This study was designed to evaluate the prospective defensive effect of lysosomal membrane stabilization by imipramine (IMP) against GTM nephrotoxicity in rats. GTM (30 mg/kg/h) was intraperitoneally administered over 4 h daily (120 mg/kg/day) for 7 days. IMP (30 mg/kg/day) was orally administered for 14 days; starting 7 days before and then concurrently with GTM. On 15th day, samples (urine, blood, kidney) were collected to estimate biomarkers of kidney function, lysosomal stability, apoptosis, and inflammation. IMP administration to GTM-treated rats ameliorated the disruption in lysosomal membrane stability induced by GTM. That was evidenced by enhanced renal protein expressions of LAMP2 and PI3K, but reduced cathepsin D cytoplasmic expression in kidney sections. Besides, IMP guarded against apoptosis in GTM-treated rats by down-regulation of the pro-apoptotic (tBid, Bax, cytochrome c) and the effector cleaved caspase-3 expressions, while the anti-apoptotic Bcl-2 expression was enhanced. Additionally, the inflammatory cascade p38 MAPK/NF-κB/TNF-α was attenuated in GTM + IMP group along with marked improvement in kidney function biomarkers, compared to GTM group. These findings were supported by the obvious improvement in histological architecture. Furthermore, in vitro enhancement of the antibacterial activity of GTM by IMP confers an additional benefit to their combination. Conclusively, lysosomal membrane stabilization by IMP with subsequent suppression of tBid/cytochrome c/cleaved caspase-3 apoptotic signaling could be a promising protective strategy against GTM nephrotoxicity.
Assuntos
Citocromos c , Imipramina , Ratos , Animais , Citocromos c/metabolismo , Imipramina/farmacologia , Gentamicinas , Caspase 3/metabolismo , Catepsina D , Regulação para Baixo , Estudos Prospectivos , Rim/patologia , Apoptose , Lisossomos/metabolismo , Biomarcadores/metabolismo , Estresse OxidativoRESUMO
Lysosomes are degradative organelles that facilitate the removal and recycling of potentially cytotoxic materials and mediate a variety of other cellular processes, such as nutrient sensing, intracellular signaling, and lipid metabolism. Due to these central roles, lysosome dysfunction can lead to deleterious outcomes, including the accumulation of cytotoxic material, inflammation, and cell death. We previously reported that cationic amphiphilic drugs, such as imipramine, alter pH and lipid metabolism within macrophage lysosomes. Therefore, the ability for imipramine to induce changes to the lipid content of isolated macrophage lysosomes was investigated, focusing on sphingomyelin, cholesterol, and glycerophospholipid metabolism as these lipid classes have important roles in inflammation and disease. The lysosomes were isolated from control and imipramine-treated macrophages using density gradient ultracentrifugation, and mass spectrometry was used to measure the changes in their lipid composition. An unsupervised hierarchical cluster analysis revealed a clear differentiation between the imipramine-treated and control lysosomes. There was a significant overall increase in the abundance of specific lipids mostly composed of cholesterol esters, sphingomyelins, and phosphatidylcholines, while lysophosphatidylcholines and ceramides were overall decreased. These results support the conclusion that imipramine's ability to change the lysosomal pH inhibits multiple pH-sensitive enzymes in macrophage lysosomes.
Assuntos
Imipramina , Esfingomielinas , Humanos , Esfingomielinas/metabolismo , Imipramina/farmacologia , Colesterol/metabolismo , Macrófagos/metabolismo , Lisossomos/metabolismo , Inflamação/metabolismo , Metabolismo dos Lipídeos , Glicerofosfolipídeos/metabolismoRESUMO
Profiling the variability related to the estrous cycle is essential for assessing depressive-like behavior and screening drugs. This study compares circulating plasma corticosterone levels [CORT] and behavioral alterations in mice exposed to sucrose preference, forced swimming, and tail suspension tests (SPT, FST, and TST, respectively). While SPT exposure did not significantly alter [CORT], FST and TST showed notable changes. Mice in the TST exhibited increased movement and decreased immobility time compared to FST, suggesting a lower likelihood of depressive-like behavior in male mice. Notably, during the proestrus phase, female mice displayed the highest tendency for depressive-like behavior and elevated [CORT], but similar response to antidepressants (imipramine and fluoxetine). The inherent stress of the FST and TST tasks appears to influence [CORT] as well as depressant and antidepressant effects. These comparisons provide valuable insights for further behavioral phenotyping, model sensitivity assessment, and deepen our neurobiological understanding of depression in the context of drug screening.
Assuntos
Antidepressivos , Fluoxetina , Camundongos , Masculino , Feminino , Animais , Antidepressivos/farmacologia , Fluoxetina/farmacologia , Depressão/tratamento farmacológico , Imipramina/farmacologia , Comportamento Animal , Natação , Modelos Animais de Doenças , Corticosterona , Elevação dos Membros PosterioresRESUMO
Ether-a-go-go (EAG) channels are key regulators of neuronal excitability and tumorigenesis. EAG channels contain an N-terminal Per-Arnt-Sim (PAS) domain that can regulate currents from EAG channels by binding small molecules. The molecular mechanism of this regulation is not clear. Using surface plasmon resonance and electrophysiology we show that a small molecule ligand imipramine can bind to the PAS domain of EAG1 channels and inhibit EAG1 currents via this binding. We further used a combination of molecular dynamics (MD) simulations, electrophysiology, and mutagenesis to investigate the molecular mechanism of EAG1 current inhibition by imipramine binding to the PAS domain. We found that Tyr71, located at the entrance to the PAS domain cavity, serves as a "gatekeeper" limiting access of imipramine to the cavity. MD simulations indicate that the hydrophobic electrostatic profile of the cavity facilitates imipramine binding and in silico mutations of hydrophobic cavity-lining residues to negatively charged glutamates decreased imipramine binding. Probing the PAS domain cavity-lining residues with site-directed mutagenesis, guided by MD simulations, identified D39 and R84 as residues essential for the EAG1 channel inhibition by imipramine binding to the PAS domain. Taken together, our study identified specific residues in the PAS domain that could increase or decrease EAG1 current inhibition by imipramine binding to the PAS domain. These findings should further the understanding of molecular mechanisms of EAG1 channel regulation by ligands and facilitate the development of therapeutic agents targeting these channels.
Assuntos
Canais de Potássio Éter-A-Go-Go , Imipramina , Fenômenos Eletrofisiológicos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/química , Canais de Potássio Éter-A-Go-Go/genética , Imipramina/química , Imipramina/farmacologia , Ligação Proteica , Animais , Domínios Proteicos , Camundongos , XenopusRESUMO
The forced swim test (FST) is a traditional assay, which has been used for more than 40 years to assess antidepressant effects of novel drug candidates. In recent years, a debate about the test has focused on the assumption that the FST is highly aversive and burdening for the animals because of the earlier anthropomorphic interpretation and designation as a "behavioral despair test". The Directive 2010/63/EU and the German Animal Welfare law require a prospective severity classification of the planned experimental procedures. Still, an objective examination of the animals' burden in this test has not been performed yet. To fill this gap, we conducted an evidence-based severity assessment of the forced swim test in rats according to a 'standard protocol' with a water temperature of 25°C. We examined parameters representing the physiological and the affective state, and natural as well as locomotion-associated behaviors in three separate experiments to reflect as many dimensions as possible of the animal's condition in the test. Hypothermia was the only effect observed in all animals exposed to the FST when using this standard protocol. Additional adverse effects on body weight, food consumption, and fecal corticosterone metabolite concentrations occurred in response to administration of the antidepressant imipramine, which is frequently used as positive control when testing for antidepressant effects of new substances. We conclude that this version of the FST itself is less severe for the animals than assumed, and we suggest a severity classification of 'moderate' because of the acute and short-lasting effects of hypothermia. To refine the FST according to the 3Rs, we encourage confirming the predictive validity in warmer water temperatures to allow the rats to maintain physiological body temperature.
Assuntos
Hipotermia , Ratos , Animais , Estudos Prospectivos , Antidepressivos/farmacologia , Imipramina/farmacologia , Natação , Água/farmacologia , Comportamento Animal/fisiologiaRESUMO
AIM: To assess the protective effects of goji berry (Lycium barbarum L.) polysaccharides (LBP) on depression-like behavior in ovariectomized rats and to elucidate the mechanisms underlying these effects. METHODS: One hundred female Wistar albino rats (three months old) were randomly assigned either to ovariectomy (n=50) or sham surgery (n=50). After a 14-day recovery period, the groups were divided into five treatment subgroups (10 per group): high-dose LBP (200 mg/kg), low-dose LBP (20 mg/kg), imipramine (IMP, 2.5 mg/kg), 17-beta estradiol (E2, 1 mg/kg), and distilled water. Then, rats underwent a forced swimming test. We also determined the levels of serum antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and malondialdehyde), E2 levels, hippocampal brain-derived neurotrophic factor (BDNF), 5HT2A receptor, and transferase dUTP nick end labeling (TUNEL)-positive cells. RESULTS: Both low-dose LBP and imipramine decreased depression-like behavior by increasing serum superoxide dismutase activity and by decreasing serum malondialdehyde level. Furthermore, low-dose LPB, high-dose LBP, and imipramine increased the number of 5-HT2A receptor- and BDNF-positive cells but decreased the number of TUNEL-positive cells in the hippocampus. CONCLUSION: This is the first study to show the antidepressant effect of LBP. Although additional research is needed, LBP may be considered a potential new antidepressant.
Assuntos
Lycium , Fármacos Neuroprotetores , Feminino , Ratos , Animais , Fármacos Neuroprotetores/farmacologia , Ratos Wistar , Fator Neurotrófico Derivado do Encéfalo , Imipramina/farmacologia , Depressão/tratamento farmacológico , Depressão/prevenção & controle , Polissacarídeos/farmacologia , MalondialdeídoRESUMO
In Alzheimer's disease (AD), reactive astrocytes produce extracellular vesicles (EVs) that affect mitochondria in neurons. Here, we show that Aß-induced generation of the sphingolipid ceramide by acid sphingomyelinase (A-SMase) triggered proinflammatory cytokine (C1q, TNF-α, IL-1α) release by microglia, which induced the reactive astrocytes phenotype and secretion of EVs enriched with ceramide. These EVs impeded the capacity of neurons to respond to energy demand. Inhibition of A-SMase with Arc39 and Imipramine reduced the secretion of cytokines from microglia, prompting us to test the effect of Imipramine on EV secretion and AD pathology in the 5xFAD mouse model. Brain derived-EVs from 5xFAD mice treated with Imipramine contained reduced levels of the astrocytic marker GFAP, ceramide, and Aß and did not impair mitochondrial respiration when compared to EVs derived from untreated 5xFAD brain. Consistently, Imipramine-treated 5xFAD mice showed reduced AD pathology. Our study identifies A-SMase inhibitors as potential AD therapy by preventing cyotokine-elicited secretion of mitotoxic EVs from astrocytes.
Assuntos
Doença de Alzheimer , Vesículas Extracelulares , Animais , Camundongos , Doença de Alzheimer/tratamento farmacológico , Astrócitos , Esfingomielina Fosfodiesterase , Imipramina/farmacologia , CeramidasRESUMO
BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) has limited treatment options. This study investigated imipramine, a tricyclic antidepressant, as a potential therapy for OSCC using a SAS-bearing xenograft animal model. MATERIALS AND METHODS: The SAS-bearing xenograft model evaluated imipramine's impact on tumor growth. The control group received no treatment, while the imipramine-treated group received regular doses. Tumor growth, confirmed by imaging, and histological analysis assessed size and weight. Imipramine's effects on apoptosis, epithelial-to-mesenchymal transition (EMT), and transcription factors (AKT, ERK, STAT3) were analyzed. RESULTS: Imipramine significantly suppressed tumor growth within 6 days of treatment, with sustained activity. Computer tomography (CT) scans and histology confirmed reduced size and weight by imipramine. Imipramine induced apoptosis via caspase-dependent/-independent pathways, inhibited EMT, and down-regulated phosphorylated AKT, ERK, and STAT3. CONCLUSION: Imipramine shows promise as an effective OSCC therapy, inhibiting tumor growth, inducing apoptosis, and inhibiting EMT. Its impact on transcription factors and modulation of the AKT/ERK/STAT3 pathway suggest a multifaceted approach.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Neoplasias Bucais/tratamento farmacológico , Imipramina/farmacologia , Proteínas Proto-Oncogênicas c-akt , Apoptose , Sistema de Sinalização das MAP Quinases , Modelos Animais de DoençasRESUMO
BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is an aggressive and deadly subtype of breast cancer, and there is an urgent need for new therapeutic strategies. The highly metastatic and anti-apoptotic characteristics are known to be the major factors causing uncontrolled growth in TNBC. Imipramine is a tricyclic antidepressant that possesses anti-inflammatory activity and has been reported to inhibit the progression of highly metastatic non-small cell lung cancer. MATERIALS AND METHODS: This study used MTT assay, apoptosis markers flow cytometry analysis, open-source data analysis, NF-B reporter gene assay, and western blotting to elucidate the effect of imipramine on MDA-MB-231 and 4T1 cells. RESULTS: Imipramine induced caspase-mediated extrinsic and intrinsic apoptosis and was potentially associated with patient overall survival. Furthermore, imipramine suppressed the invasion and migration abilities and the expression of metastasis-associated proteins in TNBC cells. CONCLUSION: Imipramine effectively suppressed TNBC progression by inducing apoptosis and inhibiting metastasis.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Imipramina/farmacologia , Imipramina/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Movimento CelularRESUMO
PURPOSE: To examine the possible role of impramine and agmatine through a mTOR signal pathway on rat ovary after maternal separation stress-induced depression. METHODS: Sprague Dawley neonatal female rats were divided into control, maternal separation (MS), MS+imipramine, and MS+agmatine groups. Rats were subjected to MS for 4 hours daily from postnatal day (PND) 2 to PND 21 and pups were exposed to social isolation (SI) on PND23 for 37 days for model establishment treated with imipramine (30 mg/kg; ip) or agmatine (40 mg/kg; ip) for 15 days. In order to examine behavioral changes rats were all subjected to locomotor activity and forced swimming tests (FST). Ovaries were isolated for morphological evaluation, follicle counting and mTOR signal pathway protein expression levels were detected. RESULTS: Increased number of primordial follicles and diminished ovarian reserve in the MS groups were detected. Imipramine treatment caused diminished ovarian reserve and atretic follicle; however, agmatine treatment provided the maintenance of ovarian follicular reserve after MS. mTOR signal pathway may have an important role during rat ovarian follicular development in model of MS. CONCLUSIONS: Our findings suggest that agmatine may help to protect ovarian reserve during follicular development by controlling cell growth.
Assuntos
Agmatina , Reserva Ovariana , Ratos , Animais , Feminino , Ratos Sprague-Dawley , Imipramina/farmacologia , Agmatina/farmacologia , Depressão/tratamento farmacológico , Depressão/etiologia , Privação Materna , Serina-Treonina Quinases TOR , Transdução de SinaisRESUMO
Clinical studies have shown that periodontitis is associated with non-alcoholic fatty liver disease (NAFLD). However, it remains unclear if periodontitis contributes to the progression of NAFLD. In this study, we generated a mouse model with high-fat diet (HFD)-induced metabolic syndrome (MetS) and NAFLD and oral P. gingivalis inoculation-induced periodontitis. Results showed that the presence of periodontitis increased insulin resistance and hepatic inflammation and exacerbated the progression of NAFLD. To determine the role of sphingolipid metabolism in the association between NAFLD and periodontitis, we also treated mice with imipramine, an inhibitor of acid sphingomyelinase (ASMase), and demonstrated that imipramine treatment significantly alleviated insulin resistance and hepatic inflammation, and improved NAFLD. Studies performed in vitro showed that lipopolysaccharide (LPS) and palmitic acid (PA), a major saturated fatty acid associated with MetS and NAFLD, synergistically increased the production of ceramide, a bioactive sphingolipid involved in NAFLD progression in macrophages but imipramine effectively reversed the ceramide production stimulated by LPS and PA. Taken together, this study showed for the first time that the presence of periodontitis contributed to the progression of NAFLD, likely due to alterations in sphingolipid metabolism that led to exacerbated insulin resistance and hepatic inflammation. This study also showed that targeting ASMase with imipramine improves NAFLD by reducing insulin resistance and hepatic inflammation.
Assuntos
Resistência à Insulina , Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Periodontite , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Síndrome Metabólica/complicações , Síndrome Metabólica/metabolismo , Fígado/metabolismo , Lipopolissacarídeos/farmacologia , Imipramina/farmacologia , Periodontite/complicações , Periodontite/metabolismo , Ácido Palmítico/farmacologia , Dieta Hiperlipídica/efeitos adversos , Esfingolipídeos/metabolismo , Ceramidas/metabolismo , Inflamação/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Iron supplementation previously demonstrated antidepressant-like effects in post-partum rats. The present study evaluates the possible synergistic antidepressant effect of sub-therapeutic dose of iron co-administered with citalopram or imipramine in female Institute of Cancer Research mice. Depression-like symptoms were induced in the forced swim (FST), tail suspension (TST), and open space swim (OSST) tests while open field test (OFT) was used to assess locomotor activity. Mice (n = 8) received iron (0.8-7.2 mg/kg), citalopram (3-30 mg/kg), imipramine (3-30 mg/kg), desferrioxamine (50 mg/kg) or saline in the single treatment phase of each model and subsequently a sub-therapeutic dose of iron co-administered with citalopram or imipramine. Assessment of serum brain derived neurotrophic factor (BDNF) and dendritic spine density was done using ELISA and Golgi staining techniques respectively. Iron, citalopram and imipramine, unlike desferrioxamine, reduced immobility score in the TST, FST and OSST without affecting locomotor activity, suggesting antidepressant-like effect. Sub-therapeutic dose of iron in combination with citalopram or imipramine further enhanced the antidepressant-like effect, producing a more rapid effect when compared to the iron, citalopram or imipramine alone. Iron, citalopram and imipramine or their combinations increased serum BDNF concentration, hippocampal neuronal count and dendritic spine densities. Our study provides experimental evidence that iron has antidepressant-like effect and sub-therapeutic dose of iron combined with citalopram or imipramine produces more rapid antidepressant-like effect. We further show that iron alone or its combination with citalopram or imipramine attenuates the neuronal loss associated with depressive conditions, increases dendritic spines density and BDNF levels. These finding suggest iron-induced neuronal plasticity in the mice brain.