RESUMEN
Carnosine is a naturally occurring endogenous dipeptide with well-recognized anti-inflammatory, antioxidant, and neuroprotective effects at the central nervous system level. To date, very few studies have been focused on the ability of carnosine to rescue and/or enhance memory. Here, we used a well-known invertebrate model system, the pond snail Lymnaea stagnalis, and a well-studied associative learning procedure, operant conditioning of aerial respiration, to investigate the ability of carnosine to enhance long-term memory (LTM) formation and reverse memory obstruction caused by an immune challenge (i.e., lipopolysaccharide [LPS] injection). Exposing snails to 1 mM carnosine for 1 h before training in addition to enhancing memory formation resulted in a significant upregulation of the expression levels of key neuroplasticity genes (i.e., glutamate ionotropic receptor N-methyl-d-aspartate [NMDA]-type subunit 1-LymGRIN1, and the transcription factor cAMP-response element-binding protein 1-LymCREB1) in snails' central ring ganglia. Moreover, pre-exposure to 1 mM carnosine before an LPS injection reversed the memory deficit brought about by inflammation, by preventing the upregulation of key targets for immune and stress response (i.e., Toll-like receptor 4-LymTLR4, molluscan defense molecule-LymMDM, heat shock protein 70-LymHSP70). Our data are thus consistent with the hypothesis that carnosine can have positive benefits on cognitive ability and be able to reverse memory aversive states induced by neuroinflammation.
Asunto(s)
Carnosina , Lipopolisacáridos , Lymnaea , Memoria a Largo Plazo , Animales , Lymnaea/efectos de los fármacos , Carnosina/farmacología , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Largo Plazo/fisiología , Lipopolisacáridos/farmacología , Ganglios de Invertebrados/efectos de los fármacos , Ganglios de Invertebrados/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Condicionamiento Operante/efectos de los fármacos , Conducta Animal/efectos de los fármacosRESUMEN
BACKGROUND: Inflammasome overactivation, multiprotein complexes that trigger inflammatory responses, plays a critical role in Major Depressive Disorder (MDD) pathogenesis and treatment responses. Indeed, different antidepressants alleviate depression-related behaviours by specifically counteracting the NLRP3 inflammasome signalling pathway. The immunomodulatory effects of vortioxetine (VTX), a multimodal antidepressant with cognitive benefits, were recently revealed to counter memory impairment induced by a peripheral lipopolysaccharide (LPS) injection 24 hours (h) postchallenge. METHODS: The potential link between VTX and NLRP3, along with other inflammasomes, remains unexplored. Hence, adult C57BL/6J male mice (n = 73) were fed with a standard or VTX-enriched diet (600 mg/kg of food, 28 days), injected with LPS (830 µg/kg) or saline, and sacrificed 6/24 h post-LPS. At these time-points, transcriptional effects of LPS and VTX's on NLRP3, NLRP1, NLRC4, AIM2 (inflammasomes), ASC and CASP1 (related subunits) and NEK7 mediator (NLRP3 regulator) were assessed in dorsal and ventral hippocampal subregions, frontal-prefrontal cortex and hypothalamus, brain regions serving behavioural-cognitive functions impaired in MDD. RESULTS: Varied expression patterns of inflammasomes were revealed, with long-term NLRP3 and ASC transcriptional changes observed in response to LPS. It was discovered that VTX counteracted the LPS-mediated NLRP3 and ASC upregulation in memory-related brain areas like the dorsal hippocampus at 24 h time-point, potentially via regulating NEK7 expression. No VTX-mediated transcriptional effects were observed on other inflammasomes, reinforcing a potentially specific modulation on the NLRP3 inflammasome signalling pathway. CONCLUSION: Thus, a novel VTX's molecular mechanism in modulating the NLRP3 inflammasome in a time- and area-specific manner in the brain was highlighted, with significant clinical implications in treating depression and cognitive impairments.
.RESUMEN
Vaccination has drastically decreased mortality due to coronavirus disease 19 (COVID-19), but not the rate of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Alternative strategies such as inhibition of virus entry by interference with angiotensin-I-converting enzyme 2 (ACE2) receptors could be warranted. Cyclodextrins (CDs) are cyclic oligosaccharides that are able to deplete cholesterol from membrane lipid rafts, causing ACE2 receptors to relocate to areas devoid of lipid rafts. To explore the possibility of reducing SARS-CoV-2 entry, we tested hydroxypropyl-ß-cyclodextrin (HPßCD) in a HEK293T-ACE2hi cell line stably overexpressing human ACE2 and Spike-pseudotyped SARS-CoV-2 lentiviral particles. We showed that HPßCD is not toxic to the cells at concentrations up to 5 mM, and that this concentration had no significant effect on cell cycle parameters in any experimental condition tested. Exposure of HEK293T-ACEhi cells to concentrations of HPßCD starting from 2.5 mM to 10 mM showed a concentration-dependent reduction of approximately 50% of the membrane cholesterol content. In addition, incubation of HEK293T-ACEhi cells with HIV-S-CoV-2 pseudotyped particles in the presence of increasing concentrations of HPßCD (from 0.1 to 10 mM) displayed a concentration-dependent effect on SARS-CoV-2 entry efficiency. Significant effects were detected at concentrations at least one order of magnitude lower than the lowest concentration showing toxic effects. These data indicate that HPßCD is a candidate for use as a SARS-CoV-2 prophylactic agent.
RESUMEN
Mounting evidence suggests a link between gut microbiota abnormalities and post-traumatic stress disorder (PTSD). However, whether and how the gut microbiota influences PTSD susceptibility is poorly understood. Here using the arousal-based individual screening model, we provide evidence for pre-trauma and post-trauma gut microbiota alterations in susceptible mice exhibiting persistent PTSD-related phenotypes. A more in-depth analysis revealed an increased abundance of bacteria affecting brain processes including myelination, and brain systems like the dopaminergic neurotransmission. Because dopaminergic dysfunctions play a key role in the pathophysiological mechanisms subserving PTSD, we assessed whether these alterations in gut microbiota composition could be associated with abnormal levels of metabolites inducing dopaminergic dysfunctions. We found high levels of the l-tyrosine-derived metabolite p-cresol exclusively in the prefrontal cortex of susceptible mice. We further uncovered abnormal levels of dopamine and DOPAC, together with a detrimental increase of dopamine D3 receptor expression, exclusively in the prefrontal cortex of susceptible mice. Conversely, we observed either resilience mechanisms aimed at counteracting these p-cresol-induced dopaminergic dysfunctions or myelination-related resilience mechanisms only in the prefrontal cortex of resilient mice. These findings reveal that gut microbiota abnormalities foster trauma susceptibility and thus it may represent a promising target for therapeutic interventions.
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Dopamina , Ratones , AnimalesRESUMEN
Drugs that target human thymidylate synthase (hTS), a dimeric enzyme, are widely used in anticancer therapy. However, treatment with classical substrate-site-directed TS inhibitors induces over-expression of this protein and development of drug resistance. We thus pursued an alternative strategy that led us to the discovery of TS-dimer destabilizers. These compounds bind at the monomer-monomer interface and shift the dimerization equilibrium of both the recombinant and the intracellular protein toward the inactive monomers. A structural, spectroscopic, and kinetic investigation has provided evidence and quantitative information on the effects of the interaction of these small molecules with hTS. Focusing on the best among them, E7, we have shown that it inhibits hTS in cancer cells and accelerates its proteasomal degradation, thus causing a decrease in the enzyme intracellular level. E7 also showed a superior anticancer profile to fluorouracil in a mouse model of human pancreatic and ovarian cancer. Thus, over sixty years after the discovery of the first TS prodrug inhibitor, fluorouracil, E7 breaks the link between TS inhibition and enhanced expression in response, providing a strategy to fight drug-resistant cancers.
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Neoplasias Ováricas , Timidilato Sintasa , Femenino , Animales , Ratones , Humanos , Sitios de Unión , Timidilato Sintasa/química , Timidilato Sintasa/metabolismo , Fluorouracilo/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores Enzimáticos/farmacologíaRESUMEN
BACKGROUND AND AIM OF THE WORK: To explore gender differences in patients suffering from anxious-depressive symptoms, Metabolic Syndrome (MetS) and Colorectal Adenomas (CRAs) in a sample of outpatients undergoing colonoscopy for screening purposes. METHODS: Cross-sectional study. 126 consecutive outpatients of both sexes undergoing colonoscopy for non-specific abdominal symptoms between January 2015 and June 2021 at the Modena Policlinico General Hospital (Modena, Northern Italy) were enrolled. MetS was diagnosed according to ATPIII and IDF criteria. Anxiety and depression were assessed with the Hospital Anxiety and Depression Scale (HADS), while the Temperament and Character Inventory (TCI) was used to study personality. The SF-36 was also included as a measure of quality of life perception. RESULTS: Among 126 outpatients (51.60% male) undergoing colonoscopy, 51 (44%) had CRAs, 54 (47%) MetS, 41 (41.40%) anxiety symptoms, 22 (22.20%) depressive symptoms and 13 (13.10%) combined anxious-depressive symptoms. HADS-Anxiety (t=2.68, p=0.01) and TCI Reward Dependence (TCI-RD) (t=3.01, p=0.00) mean scores were significantly higher in women; conversely, SF-36 Mental Component Summary scores were higher in men. CRAs were significantly prevalent in men (χ2=9.32, p=0.00) and were statistically significantly associated with male sex at the univariate logistic regression analysis (OR=3.27; p<0.01). At the multivariate logistic regression, diastolic hypertension (p<0.01) was positively associated with male sex, while TCI-RD (p=0.04) and HDL hypocholesterolemia (p=0.02) were inversely associated with male sex. CONCLUSIONS: Several significant gender differences in anxious-depressive symptoms, MetS and CRAs were found. These preliminary data suggest the need to consider gender specificities while implementing therapeutic, diagnostic, and preventive strategies.
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Adenoma , Neoplasias Colorrectales , Síndrome Metabólico , Ansiedad/epidemiología , Colonoscopía , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/epidemiología , Pacientes Ambulatorios , Calidad de Vida , Factores SexualesRESUMEN
The indoleamine 2,3-dioxygenase 1 (IDO1) metabolic circuitry, comprising the first tryptophan (Trp) catabolite L-kynurenine (Kyn) and the aryl hydrocarbon receptor (AHR), has emerged as a mechanism of cancer immune evasion. Here, we investigated the functional role of the IDO1/Kyn/AHR axis in chronic lymphocytic leukemia (CLL). Our data show that CLL cells expressed an active form of the IDO1 enzyme and microenvironmental stimuli can positively modulate its expression. Interferon (IFN)-γ induces IDO1 expression through the Jak/STAT1 pathway and mediates Kyn production concomitantly with Trp consumption in CLL-conditioned media, while INCB018424 (ruxolitinib), a JAK1/2 inhibitor, impaired both effects. To characterize the involvement of IDO1 in leukemic cell maintenance, we overexpressed IDO1 by vector transfection measuring enhanced resistance to spontaneous apoptosis. IDO1 pro-survival influence was confirmed by treating CLL cells with Kyn, which mediated the increase of induced myeloid leukemia cell differentiation protein (MCL1). Conversely, AHR silencing or its blockade via CH-223191 improved the apoptosis of leukemic clones and mitigated MCL1 expression. Moreover, Kyn-treated CLL cells are less affected by the pro-apoptotic effect of ABT-199 (venetoclax), while CH-223191 showed synergistic/additive cytotoxicity with this drug. Lastly, targeting directly MCL1 in CLL cells with AMG-176, we abrogate the pro-survival effect of Kyn. In conclusion, our data identify IDO1/Kyn/AHR signaling as a new therapeutic target for CLL, describing for the first time its role in CLL pathobiology.
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Quinurenina , Leucemia Linfocítica Crónica de Células B , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Quinurenina/metabolismo , Leucemia Linfocítica Crónica de Células B/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Triptófano/metabolismoRESUMEN
Cannabis sativa L. is increasingly emerging for its protective role in modulating neuroinflammation, a complex process orchestrated among others by microglia, the resident immune cells of the central nervous system. Phytocannabinoids, especially cannabidiol (CBD), terpenes, and other constituents trigger several upstream and downstream microglial intracellular pathways. Here, we investigated the molecular mechanisms of a CBD- and terpenes-enriched C. sativa extract (CSE) in an in vitro model of neuroinflammation. We evaluated the effect of CSE on the inflammatory response induced by exposure to lipopolysaccharide (LPS) in BV-2 microglial cells, compared with CBD and ß-caryophyllene (CAR), CB2 receptors (CB2r) inverse and full agonist, respectively. The LPS-induced upregulation of the pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α was significantly attenuated by CSE and only partially by CBD, whereas CAR was ineffective. In BV-2 cells, these anti-inflammatory effects exerted by CSE phytocomplex were only partially dependent on CB2r modulation and they were mediated by the regulation of enzymes responsible for the endocannabinoids metabolism, by the inhibition of reactive oxygen species release and the modulation of JNK/p38 cascade with consequent NF-κB p65 nuclear translocation suppression. Our data suggest that C. sativa phytocomplex and its multitarget mechanism could represent a novel therapeutic strategy for neuroinflammatory-related diseases.
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Cannabidiol , Cannabis , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Citocinas/metabolismo , Endocannabinoides/farmacología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Microglía , FN-kappa B/metabolismo , Receptor Cannabinoide CB2/metabolismoRESUMEN
This review describes the advantages of adopting a molluscan complementary model, the freshwater snail Lymnaea stagnalis, to study the neural basis of learning and memory in appetitive and avoidance classical conditioning; as well as operant conditioning of its aerial respiratory and escape behaviour. We firstly explored 'what we can teach Lymnaea' by discussing a variety of sensitive, solid, easily reproducible and simple behavioural tests that have been used to uncover the memory abilities of this model system. Answering this question will allow us to open new frontiers in neuroscience and behavioural research to enhance our understanding of how the nervous system mediates learning and memory. In fact, from a translational perspective, Lymnaea and its nervous system can help to understand the neural transformation pathways from behavioural output to sensory coding in more complex systems like the mammalian brain. Moving on to the second question: 'what can Lymnaea teach us?', it is now known that Lymnaea shares important associative learning characteristics with vertebrates, including stimulus generalization, generalization of extinction and discriminative learning, opening the possibility to use snails as animal models for neuroscience translational research.
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Aprendizaje , Lymnaea , Animales , Condicionamiento Operante , Modelos AnimalesRESUMEN
Maladaptive eating behavior is a growing public health problem and compulsively eating excessive food in a short time, or binge eating, is a key symptom of many eating disorders. In order to investigate the binge-like eating behavior in female rats, induced by intermittent food restrictions/refeeding and frustration stress, we analyzed for the first time the metabolic profile obtained from serum of rats, through nuclear magnetic resonance (NMR) spectroscopy. In this experimental protocol, rats were exposed to chow food restricting/refeeding and frustration stress manipulation. This stress procedure consists of 15 min exposure to the odor and sight of a familiar chocolate paste, without access to it, just before offering the palatable food. In this model, a "binge-eating episode" was considered the significantly higher palatable food consumption within 2 h in restricted and stressed rats (R + S) than in the other three experimental groups: rats with no food restriction and no stress (NR + NS), only stressed rats (NR + S) or only restricted rats (R + NS). Serum samples from these four different rat groups were collected. The statistical analysis of the 1 H NMR spectral profiles of the four sets of samples pointed to O- and N-acetyl glycoproteins as the main biomarkers for the discrimination of restriction effects. Other metabolites, such as threonine, glycine, glutamine, acetate, pyruvate and lactate, showed trends that may be useful to understand metabolic pathways involved in eating disorders. This study suggested that NMR-based metabolomics is a suitable approach to detect biomarkers related to binge-eating behavior.
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Trastorno por Atracón/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Metabolómica , Animales , Biomarcadores/sangre , Femenino , Lípidos/sangre , Sustancias Macromoleculares/sangre , Ratas , Ratas Sprague-DawleyRESUMEN
Background and aim of the work Colorectal mucosal precancerous lesions, metabolic syndrome (MetS) and psychiatric disorders may share a common low-grade local and systemic inflammation. Aim is to report on preliminary data concerning a research adopting a psycho-neuro-endocrine-immune (PNEI) approach to study outpatients undergoing colonoscopy. Methods A sample of patients undergoing colonoscopy was cross-sectionally investigated. Data on colorectal adenomas, MetS, early atherosclerosis, anxious-depressive symptoms, personality traits, and inflammatory markers were statistically analyzed. Results Sixty-two patients were recruited (female 50%, mean age: 60.8±9.4 years). The prevalence of adenomas and MetS was respectively of 45.2% and 41.9%. Anxiety and depressive symptoms were detected in 16 (32.7%) and 9 (18.4%) subjects, respectively. The presence of adenomas positively correlated with male sex (p=0.01), age (p<0.01), IL-6 (p=0.03), hsCRP (p=0.04), and MetS (p=0.03); it was also associated with hsCRP concentration (aOR=3.81, p=0.03). Conclusions Proinflammatory atherogenic status, psychological traits, increased mucosal inflammation, and metabolic parameters may share a common a pathogenic mechanism, worth studying.
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Adenoma , Neoplasias Colorrectales , Adenoma/epidemiología , Anciano , Ansiedad/epidemiología , Colonoscopía , Neoplasias Colorrectales/epidemiología , Depresión/epidemiología , Femenino , Humanos , Inflamación/epidemiología , Italia/epidemiología , Masculino , Síndrome Metabólico/epidemiología , Persona de Mediana Edad , Factores de RiesgoRESUMEN
An increasing number of studies show that both inflammation and neural plasticity act as key players in the vulnerability and recovery from psychiatric disorders and neurodegenerative diseases. However, the interplay between these two players has been limitedly explored. In fact, while a few studies reported an immune activation, others conveyed an immune suppression, associated with an impairment in neural plasticity. Therefore, we hypothesized that deviations in inflammatory levels in both directions may impair neural plasticity. We tested this hypothesis experimentally, by acute treatment of C57BL/6 adult male mice with different doses of two inflammatory modulators: lipopolysaccharide (LPS), an endotoxin, and ibuprofen (IBU), a nonselective cyclooxygenase inhibitor, which are respectively a pro- and an anti-inflammatory agent. The results showed that LPS and IBU have different effects on behavior and inflammatory response. LPS treatment induced a reduction of body temperature, a decrease of body weight and a reduced food and liquid intake. In addition, it led to increased levels of inflammatory markers expression, both in the total hippocampus and in isolated microglia cells, including Interleukin (IL)-1ß, and enhanced the concentration of prostaglandin E2 (PGE2). On the other hand, IBU increased the level of anti-inflammatory markers, decreased tryptophan 2,3-dioxygenase (TDO2), the first step in the kynurenine pathway known to be activated during inflammatory conditions, and PGE2 levels. Though LPS and IBU administration differently affected mediators related with pro- or anti-inflammatory responses, they produced overlapping effects on neural plasticity. Indeed, higher doses of both LPS and IBU induced a statistically significant decrease in the amplitude of long-term potentiation (LTP), in Brain-Derived Neurotrophic Factor (BDNF) expression levels and in the phosphorylation of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunit GluR1, compared to the control group. Such effect appears to be dose-dependent since only the higher, but not the lower, dose of both compounds led to a plasticity impairment. Overall, the present findings indicate that acute treatment with pro- and anti-inflammatory agents impair neural plasticity in a dose dependent manner.
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Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Inflamación/metabolismo , Potenciación a Largo Plazo/fisiología , Plasticidad Neuronal/fisiología , Animales , Antiinflamatorios/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Citocinas/inmunología , Citocinas/metabolismo , Dinoprostona/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ibuprofeno/farmacología , Inflamación/inmunología , Interleucina-1beta/metabolismo , Quinurenina/metabolismo , Lipopolisacáridos/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Plasticidad Neuronal/inmunología , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Cardiovascular diseases, anxiety, and depression are among the most frequent clinical conditions in the Western world, often in comorbidity. Evidence regarding a shared pathophysiology suggests a mediating role by chronic systemic inflammation. The aims of this study were to measure the association between anxiety and depressive symptoms, cardiovascular risk factors, and inflammatory markers. Outpatients aged 40 years or more undergoing colonoscopy after positive fecal occult blood test were enrolled; the following data were collected: body mass index, blood pressure, blood glucose, lipid profile, C-reactive protein (CRP) level, carotid thickness, Hospital Anxiety and Depression Scale, Temperament and Character Inventory, INTERdisciplinary MEDicine Self-Assessment, and 36-Item Short-Form Health Survey scores. Fifty-four patients were enrolled; 30.2% had anxiety symptoms, 18.9% depressive symptoms, and 9.4% concomitant anxiety-depressive symptoms. Anxiety symptoms were associated with low high-density lipoprotein levels. Depressive symptoms were associated with CRP levels, providing supporting evidence for the role of inflammation in the pathophysiology of depression.
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Ansiedad/epidemiología , Enfermedades Cardiovasculares/epidemiología , Depresión/epidemiología , Encuestas Epidemiológicas , Adulto , Anciano , Anciano de 80 o más Años , Ansiedad/sangre , Ansiedad/psicología , Proteína C-Reactiva/metabolismo , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/psicología , Estudios Transversales , Depresión/sangre , Depresión/psicología , Femenino , Encuestas Epidemiológicas/métodos , Humanos , Italia/epidemiología , Lipoproteínas HDL/sangre , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
An increasing number of studies show that selective serotonin reuptake inhibitors (SSRIs) exert their therapeutic action, at least in part, by amplifying the influence of the living environment on mood. As a consequence, when administered in a favorable environment, SSRIs lead to a reduction of symptoms, but in stressful conditions, they show limited efficacy. Therefore, novel therapeutic approaches able to neutralize the influence of the stressful environment on treatment are needed. The aim of our study was to test whether, in a mouse model of depression, the combined administration of SSRI fluoxetine and metformin, a drug able to improve the metabolic profile, counteracts the limited efficacy of fluoxetine alone when administered in stressful conditions. Indeed, metabolic alterations are associated to both the onset of major depression and the antidepressant efficacy. To this goal, adult C57BL/6 male mice were exposed to stress for 6 weeks; the first two weeks was aimed at generating a mouse model of depression. During the remaining 4 weeks, mice received one of the following treatments: vehicle, fluoxetine, metformin, or a combination of fluoxetine and metformin. We measured liking- and wanting-type anhedonia as behavioral phenotypes of depression and assessed the expression levels of selected genes involved in major depressive disorder and antidepressant response in the dorsal and ventral hippocampus, which are differently involved in the depressive symptomatology. The combined treatment was more effective than fluoxetine alone in ameliorating the depressive phenotype after one week of treatment. This was associated to an increase in IGF2 mRNA expression and enhanced long-term potentiation, specifically in the dorsal hippocampus, at the end of treatment. Overall, the present results show that, when administered in stressful conditions, the combined fluoxetine and metformin treatment may represent a more effective approach than fluoxetine alone in a short term. Finally, our findings highlight the relevance of polypharmacological strategy as effective interventions to increase the efficacy of the antidepressant drugs currently available.
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Anhedonia/efectos de los fármacos , Antidepresivos/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Fluoxetina/uso terapéutico , Hipocampo/efectos de los fármacos , Factor II del Crecimiento Similar a la Insulina/metabolismo , Metformina/uso terapéutico , Animales , Antidepresivos/farmacología , Trastorno Depresivo/metabolismo , Modelos Animales de Enfermedad , Quimioterapia Combinada , Fluoxetina/farmacología , Hipocampo/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Masculino , Metformina/farmacología , Ratones , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) have been studied as possible adjunctive therapy in the treatment of depression. However, administering NSAIDs to increase the effectiveness of antidepressant has yielded inconsistent results. METHODS: We evaluated the effect of the co-administration of fluoxetine (5â¯mg/kg) and flurbiprofen (5â¯mg/kg) or fluoxetine (5â¯mg/kg) and celecoxib (5â¯mg/kg) in the chronic escape deficit (CED) model of depression after 7 days of treatment. The co-administration of fluoxetine plus acetylsalicylic acid (ASA, 45â¯mg/kg i.p.) was used as a positive control. Moreover, we tested the behavioral effect of different doses (45, 22.5, and 11.25â¯mg/Kg i.p.) of ASA as potentiating agent of the effect of fluoxetine in the same paradigm. RESULTS: Our study showed that only the co-administration of ASA with fluoxetine was able to revert the stress-induced condition of escape deficit after 7 days of treatment, and that the amplitude of the antidepressant-like effect of ASA was dose dependent. In the same experimental conditions, celecoxib with fluoxetine only partially resolved the stress-induced impaired behavior while flurbiprofen/fluoxetine cotreatment was ineffective. LIMITATIONS: Our study is still exploratory, more doses, longer treatment regimens, and different behavioral outcomes must be investigated to draw a clear conclusion. CONCLUSION: Our results further stress the importance of the type and dose when NSAIDs are associated with antidepressants to ameliorate a clinical response.
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Antiinflamatorios/administración & dosificación , Antidepresivos/administración & dosificación , Depresión/tratamiento farmacológico , Fluoxetina/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Celecoxib/administración & dosificación , Modelos Animales de Enfermedad , Quimioterapia Combinada , Flurbiprofeno/administración & dosificación , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Converging evidence points at hypothalamus-pituitary-adrenal (HPA) axis hyperactivity and neuroinflammation as important factors involved in the etiopathogenesis of major depressive disorder (MDD) and in therapeutic efficacy of antidepressants. In this study, we examined the molecular effects associated with a response to a week-long treatment with escitalopram in the chronic escape deficit (CED) model, a validated model of depression based on the induction of an escape deficit after exposure of rats to an unavoidable stress. We confirmed our previous result that a treatment with escitalopram (10mg/kg) was effective after 7days in reverting the stress-induced escape deficit in approximately 50% of the animals, separating responders from non-responders. Expression of markers of HPA axis functionality as well as several inflammatory mediators were evaluated in the hypothalamus, a key structure integrating signals from the neuro, immune, endocrine systems. In the hypothalamus of responder animals we observed a decrease in the expression of CRH and its receptors and an increase in GR protein in total and nuclear extracts; this effect was accompanied by a significant decrease in circulating corticosterone in the same cohort. Hypothalamic IL-1ß and TNFα expression were increased in stressed animals, while CXCL2, IL-6, and ADAM17 mRNA levels were decreased in escitalopram treated rats regardless of the treatment response. These data suggest that efficacy of a one week treatment with escitalopram may be partially mediated by a decrease HPA axis activity, while in the hypothalamus the drug-induced effects on the expression of immune modulators did not correlate with the behavioural outcome.
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Citalopram/metabolismo , Citalopram/farmacología , Depresión/tratamiento farmacológico , Hormona Adrenocorticotrópica/metabolismo , Animales , Antidepresivos/uso terapéutico , Corticosterona/análisis , Corticosterona/sangre , Corticosterona/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Depresión/metabolismo , Trastorno Depresivo Mayor/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Hipotálamo/metabolismo , Masculino , Sistema Hipófiso-Suprarrenal/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Estrés Psicológico/complicacionesRESUMEN
Both increased inflammation and reduced neurogenesis have been associated with the pathophysiology of major depression. We have previously described how interleukin-1 (IL-1) ß, a pro-inflammatory cytokine increased in depressed patients, decreases neurogenesis in human hippocampal progenitor cells. Here, using the same human in vitro model, we show how omega-3 (ω-3) polyunsaturated fatty acids and conventional antidepressants reverse this reduction in neurogenesis, while differentially affecting the kynurenine pathway. We allowed neural cells to proliferate for 3days and further differentiate for 7days in the presence of IL-1ß (10ng/ml) and either the selective serotonin reuptake inhibitor sertraline (1µM), the serotonin and norepinephrine reuptake inhibitor venlafaxine (1µM), or the ω-3 fatty acids eicosapentaenoic acid (EPA, 10µM) or docosahexaenoic acid (DHA, 10µM). Co-incubation with each of these compounds reversed the IL-1ß-induced reduction in neurogenesis (DCX- and MAP2-positive neurons), indicative of a protective effect. Moreover, EPA and DHA also reversed the IL-1ß-induced increase in kynurenine, as well as mRNA levels of indolamine-2,3-dioxygenase (IDO); while DHA and sertraline reverted the IL-1ß-induced increase in quinolinic acid and mRNA levels of kynurenine 3-monooxygenase (KMO). Our results show common effects of monoaminergic antidepressants and ω-3 fatty acids on the reduction of neurogenesis caused by IL-1ß, but acting through both common and different kynurenine pathway-related mechanisms. Further characterization of their individual properties will be of benefit towards improving a future personalized medicine approach.
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Antidepresivos/farmacología , Ácidos Grasos Omega-3/farmacología , Neurogénesis/efectos de los fármacos , Antidepresivos/metabolismo , Técnicas de Cultivo de Célula/métodos , Citocinas/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/metabolismo , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Ácidos Grasos Omega-3/metabolismo , Hipocampo/metabolismo , Humanos , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Quinurenina/efectos de los fármacos , Quinurenina/metabolismo , Neurogénesis/fisiología , Células Madre/metabolismoRESUMEN
Binge eating episodes are characterized by uncontrollable, distressing eating of a large amount of highly palatable food and represent a central feature of bingeing related eating disorders. Research suggests that inflammation plays a role in the onset and maintenance of eating-related maladaptive behavior. Markers of inflammation can be selectively altered in discrete brain regions where they can directly or indirectly regulate food intake. In the present study, we measured expression levels of different components of cytokine systems (IL-1, IL-6, IL-18, TNF-α and IFN-É£) and related molecules (iNOS and COX2) in the preoptic and anterior-tuberal parts of the hypothalamus of a validated animal model of binge eating. In this animal model, based on the exposure to both food restriction and frustration stress, binge-like eating behavior for highly palatable food is not shown when animals are exposed to the frustration stress during the estrus phase. We found a characteristic down-regulation of the IL-18/IL-18 receptor system (with increased expression of the inhibitor of the pro-inflammatory cytokine IL-18, IL-18BP, together with a decreased expression of the binding chain of the IL-18 receptor) and a three-fold increase in the expression of iNOS specifically in the anterior-tuberal region of the hypothalamus of animals that develop a binge-like eating behavior. Differently, when food restricted animals were stressed during the estrus phase, IL-18 expression increased, while iNOS expression was not significantly affected. Considering the role of this region of the hypothalamus in controlling feeding related behavior, this can be relevant in eating disorders and obesity. Our data suggest that by targeting centrally selected inflammatory markers, we may prevent that disordered eating turns into a full blown eating disorder.
Asunto(s)
Bulimia/patología , Citocinas/metabolismo , Regulación hacia Abajo/fisiología , Hipotálamo/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Análisis de Varianza , Animales , Peso Corporal/fisiología , Bulimia/fisiopatología , Citocinas/genética , Modelos Animales de Enfermedad , Ingestión de Alimentos/fisiología , Ciclo Estral/fisiología , Femenino , Privación de Alimentos , Óxido Nítrico Sintasa de Tipo II/genética , ARN Mensajero/metabolismo , Ratas Sprague-DawleyRESUMEN
It has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these act either as anti- or pro-inflammatory drugs. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and the environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti- and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that the effects of fluoxetine treatment on inflammation and microglial function, as compared to vehicle, were dependent on the quality of the living environment. In particular, fluoxetine administered in the enriched condition increased the expression of pro-inflammatory markers compared to vehicle, while treatment in a stressful condition produced anti-inflammatory effects. These findings provide new insights regarding the effects of SSRIs on inflammation, which may be crucial to devise pharmacological strategies aimed at enhancing antidepressant efficacy by means of controlling environmental conditions.
Asunto(s)
Encefalitis/metabolismo , Ambiente , Fluoxetina/administración & dosificación , Microglía/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Animales , Citocinas/metabolismo , Depresión , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Mediadores de Inflamación/metabolismo , Masculino , Ratones Endogámicos C57BL , Microglía/fisiología , Estrés PsicológicoRESUMEN
UNLABELLED: The proinflammatory cytokine IL-18 has central anorexigenic effects and was proposed to contribute to loss of appetite observed during sickness. Here we tested in the mouse the hypothesis that IL-18 can decrease food intake by acting on neurons of the bed nucleus of the stria terminalis (BST), a component of extended amygdala recently shown to influence feeding via its projections to the lateral hypothalamus (LH). We found that both subunits of the heterodimeric IL-18 receptor are highly expressed in the BST and that local injection of recombinant IL-18 (50 ng/ml) significantly reduced c-fos activation and food intake for at least 6 h. Electrophysiological experiments performed in BST brain slices demonstrated that IL-18 strongly reduces the excitatory input on BST neurons through a presynaptic mechanism. The effects of IL-18 are cell-specific and were observed in Type III but not in Type I/II neurons. Interestingly, IL-18-sensitve Type III neurons were recorded in the juxtacapsular BST, a region that contains BST-LH projecting neurons. Reducing the excitatory input on Type III GABAergic neurons, IL-18 can increase the firing of glutamatergic LH neurons through a disinhibitory mechanism. Imbalance between excitatory and inhibitory activity in the LH can induce changes in food intake. Effects of IL-18 were mediated by the IL-18R because they were absent in neurons from animals null for IL-18Rα (Il18ra(-/-)), which lack functional IL-18 receptors. In conclusion, our data show that IL-18 may inhibit feeding by inhibiting the activity of BST Type III GABAergic neurons. SIGNIFICANCE STATEMENT: Loss of appetite during sickness is a common and often debilitating phenomenon. Although proinflammatory cytokines are recognized as mediators of these anorexigenic effects, their mechanism and sites of action remain poorly understood. Here we show that interleukin 18, an anorexigenic cytokine, can act on neurons of the bed nucleus of the stria terminalis to reduce food intake via the IL-18 receptor. The findings identify a site and a mode of action that indicate targets for the treatment of cachexia or other eating disorders.