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1.
Cancer Cell Int ; 23(1): 15, 2023 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-36726173

RESUMEN

While positive social-behavioral factors predict longer survival in cancer patients, the underlying mechanisms are unknown. Since tumor metastasis are the major cancer mortality factor, we investigated how an enriched environment (EE) conductive to enhanced sensory, cognitive and motor stimulation impact metastatic progression in lungs following intravasation in the circulation. We find that mice housed in EE exhibited reduced number of lung metastatic foci compared to control mice housed in a standard environment (SE). Compared to SE mice, EE mice increased lung inflammation as early as 4 days after circulating tumor cells extravasation. The impact of environmental signals on lung metastasis is independent of adrenergic receptors signaling. By contrast, we find that serum corticosterone levels are lower in EE mice and that glucocorticoid receptor (GR) antagonist reduces the number of lung metastasis in SE mice. In addition, the difference of the number of lung metastasis between SE and EE mice is abolished when inflammatory monocytes are rendered deficient in GR signaling. This decreased GR signaling in inflammatory monocytes of SE mice results in an exacerbated inflammatory profile in the lung. Our study shows that not only EE reduces late stages of metastatic progression in lungs but disclose a novel anti-tumor mechanism whereby GR-dependent reprogramming of inflammatory monocytes can inhibit metastatic progression in lungs. Moreover, while inflammatory monocytes have been shown to promote cancer progression, they also have an anti-tumor effect, suggesting that their role is more complex than currently thought.

2.
Neuroimmunomodulation ; 26(2): 59-66, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30703773

RESUMEN

BACKGROUND: Others and we have shown that T cells have an important role in hippocampal synaptic plasticity, including neurogenesis in the dentate gyrus, spinogenesis, and glutamatergic synaptic function in the CA of the hippocampus. Hippocampus plasticity is particularly involved in the brain effects of the enriched environment (EE), and interestingly CD4+ and CD8+ T cells play essential and differential roles in these effects. However, the precise mechanisms by which they act on the brain remain elusive. OBJECTIVES: We searched for a putative mechanism of action by which CD4+ T cells could influence brain plasticity and hypothesized that they could regulate protein transport at the level of the blood-CSF barrier in the choroid plexus. METHOD: We compared mice housed in EE and deprived of CD4+ T cells using a depleting antibody with a control group injected with the control isotype. We analyzed in the hippocampus the gene expression profiles using the Agilent system, and the expression of target proteins in plasma, CSF, and the choroid plexus using ELISA. RESULTS: We show that CD4+ T cells may influence EE-induced hippocampus plasticity via thyroid hormone signaling by regulating in the choroid plexus the expression of transthyretin, the major transporter of thyroxine (T4) to the brain parenchyma. CONCLUSIONS: Our study highlights the contribution of close interactions between the immune and neuroendocrine systems in brain plasticity and function.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Plexo Coroideo/metabolismo , Plasticidad Neuronal/fisiología , Prealbúmina/metabolismo , Tiroxina/metabolismo , Animales , Femenino , Hipocampo/metabolismo , Vivienda para Animales , Ratones , Ratones Endogámicos C57BL , Transporte de Proteínas/fisiología , Hormonas Tiroideas/metabolismo
3.
Brain Behav Immun ; 69: 235-254, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29175168

RESUMEN

Enriched environment (EE) induces plasticity changes in the brain. Recently, CD4+ T cells have been shown to be involved in brain plasticity processes. Here, we show that CD8+ T cells are required for EE-induced brain plasticity in mice, as revealed by measurements of hippocampal volume, neurogenesis in the DG of the hippocampus, spinogenesis and glutamatergic synaptic function in the CA of the hippocampus. As a consequence, EE-induced behavioral benefits depend, at least in part, on CD8+ T cells. In addition, we show that spleen CD8+ T cells from mice housed in standard environment (SE) and EE have different properties in terms of 1) TNFα release after in vitro CD3/CD28 or PMA/Iono stimulation 2) in vitro proliferation properties 3) CD8+ CD44+ CD62Llow and CD62Lhi T cells repartition 4) transcriptomic signature as revealed by RNA sequencing. CD8+ T cells purified from the choroid plexus of SE and EE mice also exhibit different transcriptomic profiles as highlighted by single-cell mRNA sequencing. We show that CD8+ T cells are essential mediators of beneficial EE effects on brain plasticity and cognition. Additionally, we propose that EE differentially primes CD8+ T cells leading to behavioral improvement.


Asunto(s)
Conducta Animal/fisiología , Linfocitos T CD8-positivos/metabolismo , Ambiente , Hipocampo/fisiología , Neurogénesis/fisiología , Plasticidad Neuronal/fisiología , Animales , Proliferación Celular/fisiología , Conducta Alimentaria/fisiología , Femenino , Ratones , Actividad Motora/fisiología
4.
Brain Behav Immun ; 50: 275-287, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26209808

RESUMEN

Regulation of neuroinflammation by glial cells plays a major role in the pathophysiology of major depression. While astrocyte involvement has been well described, the role of microglia is still elusive. Recently, we have shown that Adiponectin (ApN) plays a crucial role in the anxiolytic/antidepressant neurogenesis-independent effects of enriched environment (EE) in mice; however its mechanisms of action within the brain remain unknown. Here, we show that in a murine model of depression induced by chronic corticosterone administration, the hippocampus and the hypothalamus display increased levels of inflammatory cytokines mRNA, which is reversed by EE housing. By combining flow cytometry, cell sorting and q-PCR, we show that microglia from depressive-like mice adopt a pro-inflammatory phenotype characterized by higher expression levels of IL-1ß, IL-6, TNF-α and IκB-α mRNAs. EE housing blocks pro-inflammatory cytokine gene induction and promotes arginase 1 mRNA expression in brain-sorted microglia, indicating that EE favors an anti-inflammatory activation state. We show that microglia and brain-macrophages from corticosterone-treated mice adopt differential expression profiles for CCR2, MHC class II and IL-4recα surface markers depending on whether the mice are kept in standard environment or EE. Interestingly, the effects of EE were abolished when cells are isolated from ApN knock-out mouse brains. When injected intra-cerebroventricularly, ApN, whose level is specifically increased in cerebrospinal fluid of depressive mice raised in EE, rescues microglia phenotype, reduces pro-inflammatory cytokine production by microglia and blocks depressive-like behavior in corticosterone-treated mice. Our data suggest that EE-induced ApN increase within the brain regulates microglia and brain macrophages phenotype and activation state, thus reducing neuroinflammation and depressive-like behaviors in mice.


Asunto(s)
Adiponectina/metabolismo , Depresión/metabolismo , Encefalitis/metabolismo , Ambiente , Hipocampo/metabolismo , Hipotálamo/metabolismo , Macrófagos/metabolismo , Microglía/metabolismo , Adiponectina/administración & dosificación , Adiponectina/genética , Animales , Corticosterona/administración & dosificación , Citocinas/metabolismo , Depresión/inducido químicamente , Depresión/complicaciones , Encefalitis/complicaciones , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , ARN Mensajero/metabolismo
5.
J Neuroinflammation ; 11: 132, 2014 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-25065370

RESUMEN

BACKGROUND: Genetic and environmental factors are critical elements influencing the etiology of major depression. It is now accepted that neuroinflammatory processes play a major role in neuropsychological disorders. Neuroinflammation results from the dysregulation of the synthesis and/or release of pro- and anti-inflammatory cytokines with central or peripheral origin after various insults. Systemic bacterial lipopolysaccharide (LPS) challenge is commonly used to study inflammation-induced depressive-like behaviors in rodents. In the present study, we investigated immune-to-brain communication in mice by examining the effects of peripheral LPS injection on neuroinflammation encompassing cytokine and chemokine production, microglia and central nervous system (CNS)-associated phagocyte activation, immune cell infiltration and serotonergic neuronal function. METHODS: LPS was administered to C57BL/6 J mice by intraperitoneal injection; brains were collected and pro-inflammatory cytokine mRNA and proteins were measured. To examine the relative contribution of the different populations of brain immune cells to the occurrence of neuroinflammation after acute systemic inflammation, we precisely characterized them by flow cytometry, studied changes in their proportions and level of activation, and measured the amount of cytokines they released by Cytometric Bead Array™ after cell sorting and ex vivo culture. Because of the central role that the chemokine CCL2 seems to play in our paradigm, we studied the effect of CCL2 on the activity of serotonergic neurons of the raphe nucleus using electrophysiological recordings. RESULTS: We report that systemic LPS administration in mice caused a marked increase in pro-inflammatory IL-1ß, IL-6, TNFα and CCL2 (monocyte chemoattractant protein-1) mRNA and protein levels in the brain. Moreover, we found that LPS caused microglia and CNS-associated phagocyte activation characterized by upregulation of CCR2, TLR4/CD14, CD80 and IL-4Rα, associated with overproduction of pro-inflammatory cytokines and chemokines, especially CCL2. LPS also induced a marked and selective increase of CCR2(+) inflammatory monocytes within the brain. Finally, we showed that CCL2 hyperpolarized serotonergic raphe neurons in mouse midbrain slices, thus probably reducing the serotonin tone in projection areas. CONCLUSION: Together, we provide a detailed characterization of the molecular and cellular players involved in the establishment of neuroinflammation after systemic injection of LPS. This highlights the importance of the CCL2/CCR2 signaling and suggests a possible link with depressive disorders.


Asunto(s)
Quimiocina CCL2/metabolismo , Citocinas/metabolismo , Encefalitis/inducido químicamente , Encefalitis/patología , Lipopolisacáridos/toxicidad , Receptores CCR2/metabolismo , Animales , Antígenos CD/metabolismo , Quimiocina CCL2/genética , Citocinas/genética , Femenino , Citometría de Flujo , Técnicas In Vitro , Potenciales de la Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Neuronas/fisiología , Técnicas de Placa-Clamp , Fagocitos/efectos de los fármacos , Fagocitos/metabolismo , ARN Mensajero/metabolismo , Núcleos del Rafe/citología , Receptores CCR2/genética , Serotonina/metabolismo
6.
Microbiome ; 9(1): 157, 2021 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-34238386

RESUMEN

BACKGROUND: Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice. RESULTS: Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice. CONCLUSIONS: The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD. Video abstract.


Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Microbioma Gastrointestinal , Animales , Trastorno Autístico/etiología , Cresoles , Trasplante de Microbiota Fecal , Humanos , Ratones
7.
Metabolism ; 103: 154027, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31778708

RESUMEN

OBJECTIVE: Glucocorticoids (GCs) are highly effective anti-inflammatory and immunosuppressive drugs. However, prolonged GC therapy may cause numerous adverse effects leading to diabetes and obesity, as well as bone disorders such as osteoporosis in adults and growth retardation in children and adolescents. Prevention and care of the GC-induced adverse effects remain challenging. We have previously demonstrated the efficacy of a treatment with a non-peptidic agonist of adiponectin receptors, AdipoRon, to reverse behaviour disorders and fat mass gain induced by long-term GC treatment. In this work, we have established a relevant model of GC-induced growth and metabolic disorders and determined that AdipoRon is a potential therapeutic tool to reverse these metabolic disturbances. METHODS: 5-Week-old mice were treated continuously with or without corticosterone (35 mg/L) in drinking water for seven consecutive weeks. Taking advantage of this mouse model displaying various growth and metabolic disorders, we assayed whether AdipoRon (daily intraperitoneal injection of 1 mg/kg/day for the last 20 days) might prevent the GC-induced adverse effects. The control group was treated with vehicle only. Nutritional behaviors and metabolic parameters were followed-up throughout the treatment. Serum insulin and leptin levels were measured by ELISA. Computed tomography and histological analysis of adipose tissue were assessed at the end of the experimental procedure. RESULTS: We found that GC treatment in young mice resulted in continuously increased body weight gain associated with a food intake increase. Compared to vehicle-, GC-treated mice displayed early major hyperleptinemia (up to 6-fold more) and hyperinsulinemia (up to 20-fold more) maintained throughout the treatment. At the end of the experimental procedure, GC-treated mice displayed bone growth retardation (e.g. femur length 15.1 versus 14.0 mm, P < 0.01), higher abdominal adipose tissue volume (4.1 versus 2.3, P < 0.01) and altered glucose metabolism compared to control mice. Interestingly, AdipoRon prevented GC-induced effects on energy metabolism such as abdominal adiposity, insulinemia and leptinemia. However, AdipoRon failed to counteract bone growth retardation. CONCLUSION: We characterized the very early pathological steps induced by long-term GC in young mice in a relevant model, including growth retardation, fat mass gain and glucose homeostasis dysregulation. The adiponectin system stimulation enabled normalization of the adipose tissue and metabolic features of GC-treated mice. Adiponectin receptor agonists such as AdipoRon might constitute a novel way to counteract some GC-induced adverse effects.


Asunto(s)
Metabolismo de los Hidratos de Carbono/efectos de los fármacos , Glucocorticoides , Glucosa/metabolismo , Trastornos del Crecimiento/inducido químicamente , Obesidad/prevención & control , Piperidinas/farmacología , Grasa Abdominal/efectos de los fármacos , Grasa Abdominal/metabolismo , Animales , Desarrollo Óseo/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Trastornos del Crecimiento/metabolismo , Trastornos del Crecimiento/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Receptores de Adiponectina/agonistas
8.
Sci Rep ; 10(1): 8190, 2020 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-32424163

RESUMEN

The Phospholipase A2 Receptor 1 (PLA2R1) was first identified for its ability to bind some secreted PLA2s (sPLA2s). It belongs to the C-type lectin superfamily and it binds different types of proteins. It is likely a multifunctional protein that plays a role i) in inflammation and inflammatory diseases, ii) in cellular senescence, a mechanism participating in aging and age-related diseases including cancer, and iii) in membranous nephropathy (MN), a rare autoimmune kidney disease where PLA2R1 is the major autoantigen. To help study the role of PLA2R1 in these pathophysiological conditions, we have generated a versatile NeoR-hPLA2R1 conditional transgenic mice which will allow the specific expression of human PLA2R1 (hPLA2R1) in relevant organs and cells following Cre recombinase-driven excision of the NeoR-stop cassette flanked by LoxP sites. Proof-of-concept breeding of NeoR-hPLA2R1 mice with the ubiquitous adenoviral EIIa promoter-driven Cre mouse line resulted in the expected excision of the NeoR-stop cassette and the expression of hPLA2R1 in all tested tissues. These Tg-hPLA2R1 animals breed normally, with no reproduction or apparent growth defect. These models, especially the NeoR-hPLA2R1 conditional transgenic mouse line, will facilitate the future investigation of PLA2R1 functions in relevant pathophysiological contexts, including inflammatory diseases, age-related diseases and MN.


Asunto(s)
Modelos Animales de Enfermedad , Receptores de Fosfolipasa A2/genética , Animales , Expresión Génica , Técnicas de Genotipaje , Humanos , Ratones , Ratones Transgénicos , Especificidad de Órganos
9.
J Neurochem ; 109(3): 819-25, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19309437

RESUMEN

Controversial debates still remain around the nature of the etiologic agent responsible for Amyotrophic lateral sclerosis/Parkinson dementia complex (ALS/PDC) whose incidence is unusually high among the population of the pacific island of Guam. It has been hypothesized that the neurotoxin beta-N-methylamino-L-alanine (L-BMAA) produced by cyanobacteria in the roots of Cycas Circinalis seeds might trigger ALS/PDC. Frequently observed in patients with ALS/PDC, retinopathy is one of the clinical features of the disease. The effect of the L-BMAA on cell viability was examined in vivo by measuring the electrophysiological activity of the mouse retinal neurons by electroretinography recordings. Intra-ocular injections of L-BMAA selectively reduced the b-wave amplitude, without affecting neither the a-wave amplitude nor the a- and b-latencies. The cell death of retinal cells was evidenced by histology on retina sections, caspase 3 activation, incorporation of propidium iodide and production of reactive oxygen species. Co-injection with the specific NMDA antagonist, MK-801, significantly protected the retinal neurons from L-BMAA/NMDA-induced apoptosis. We provide evidence that L-BMAA induced neuronal cell death in vivo supporting a direct causal link between L-BMAA and neuronal damages.


Asunto(s)
Aminoácidos Diaminos/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Neuronas/efectos de los fármacos , Retina/citología , Animales , Caspasa 3/metabolismo , Muerte Celular/efectos de los fármacos , Toxinas de Cianobacterias , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Electrooculografía/métodos , Potenciales Evocados/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Etiquetado Corte-Fin in Situ/métodos , Ratones , Ratones Endogámicos C57BL , Propidio , Especies Reactivas de Oxígeno/metabolismo , Factores de Tiempo
10.
J Virol ; 82(17): 8933-6, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18579603

RESUMEN

The involvement of immune cells in prion capture and transport to lymphoid tissues still remains unclear. To investigate the role of dendritic cells (DC), we used DTR(+/+) mice, a transgenic model designed to trigger short-term ablation of DC. Transient depletion of DC around the time of intraperitoneal infection delayed prion replication in the spleen, as followed by PrPsc amount, a specific hallmark of prion diseases. Consequently, neuroinvasion and incubation time of prion disease were delayed. In contrast, no differences were observed after oral infection. These results suggest that DC act as vectors for prions from the peripheral entry site to the spleen.


Asunto(s)
Células Dendríticas/inmunología , Células Dendríticas/fisiología , Priones/patogenicidad , Scrapie/etiología , Scrapie/transmisión , Animales , Antígeno CD11c/metabolismo , Inyecciones Intraperitoneales , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Proteínas PrPSc/análisis , Priones/administración & dosificación , Scrapie/inmunología , Scrapie/patología , Bazo/patología
11.
Acta Neuropathol Commun ; 7(1): 153, 2019 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-31610810

RESUMEN

Major depressive disorder (MDD) is one of the most frequent psychiatric illnesses, leading to reduced quality of life, ability to work and sociability, thus ranking among the major causes of disability and morbidity worldwide. To date, genetic and environmental determinants of MDD remain mostly unknown. Here, we investigated whether and how the Plasminogen Activator Inhibitor-1 (PAI-1) may contribute to MDD. We first examined the phenotype of PAI-1 knockout (PAI-1-/-) and wild-type (PAI-1+/+) male mice with a range of behavioral tests assessing depressive-like behaviors (n = 276). We next investigated the mechanisms relating PAI-1 to MDD using molecular, biochemical and pharmacological analyzes. We demonstrate here that PAI-1 plays a key role in depression by a mechanism independent of the tissue-type Plasminogen Activator (tPA) - Brain-Derived Neurotrophic Factor (BDNF) axis, but associated with impaired metabolisms of serotonin and dopamine. Our data also reveal that PAI-1 interferes with therapeutic responses to selective serotonin reuptake inhibitors (escitalopram, fluoxetine). We thus highlight a new genetic preclinical model of depression, with the lack of PAI-1 as a factor of predisposition to MDD. Altogether, these original data reveal that PAI-1 should be now considered as a key player of MDD and as a potential target for the development of new drugs to cure depressive patients resistant to current treatments.


Asunto(s)
Encéfalo/metabolismo , Trastorno Depresivo Mayor/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Depresión/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Inhibidor 1 de Activador Plasminogénico/genética , Serotonina/metabolismo , Activador de Tejido Plasminógeno/metabolismo
12.
J Neurosci ; 27(36): 9537-44, 2007 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-17804615

RESUMEN

Prion diseases are transmissible neurodegenerative disorders characterized by the accumulation in the CNS of the protease-resistant prion protein (PrPres), a structurally misfolded isoform of its physiological counterpart PrPsen. Both neuropathogenesis and prion infectivity are related to PrPres formation. Here, we report that the nonpsychoactive cannabis constituent cannabidiol (CBD) inhibited PrPres accumulation in both mouse and sheep scrapie-infected cells, whereas other structurally related cannabinoid analogs were either weak inhibitors or noninhibitory. Moreover, after intraperitoneal infection with murine scrapie, peripheral injection of CBD limited cerebral accumulation of PrPres and significantly increased the survival time of infected mice. Mechanistically, CBD did not appear to inhibit PrPres accumulation via direct interactions with PrP, destabilization of PrPres aggregates, or alteration of the expression level or subcellular localization of PrPsen. However, CBD did inhibit the neurotoxic effects of PrPres and affected PrPres-induced microglial cell migration in a concentration-dependent manner. Our results suggest that CBD may protect neurons against the multiple molecular and cellular factors involved in the different steps of the neurodegenerative process, which takes place during prion infection. When combined with its ability to target the brain and its lack of toxic side effects, CBD may represent a promising new anti-prion drug.


Asunto(s)
Cannabidiol/farmacología , Neuronas/efectos de los fármacos , Priones/efectos de los fármacos , Priones/toxicidad , Scrapie/tratamiento farmacológico , Animales , Cannabidiol/uso terapéutico , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes Neurológicos , Microglía/efectos de los fármacos , Degeneración Nerviosa/tratamiento farmacológico , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Priones/metabolismo , Scrapie/metabolismo , Ovinos , Tasa de Supervivencia , Resultado del Tratamiento
13.
Biochim Biophys Acta ; 1774(9): 1118-27, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17707142

RESUMEN

There is increasing evidence that soluble oligomers of misfolded protein may play a role in the pathogenesis of protein misfolding diseases including the transmissible spongiform encephalopathies (TSE) where the protein involved is the prion protein, PrP. The effect of oxidation on fibrillation tendency and neurotoxicity of different molecular variants of the prion peptide PrP106-126 was investigated. It was found that methionine oxidation significantly reduced amyloid fibril formation and proteinase K resistance, but it did not reduce (but rather increase slightly) the neurotoxicity of the peptides in vivo (electroretinography after intraocular injections in mice) and in vitro (in primary neuronal cultures). We furthermore found that the bovine variant of PrP106-126, containing only one methionine residue, showed both reduced fibril forming capacity and in vivo and in vitro neurotoxicity. The findings imply (I) that there is not a simple relation between the formation of amyloid fibrils and neurotoxicity of PrP106-126 derived peptides, (II) that putative, soluble, non-amyloid protofibrils, presumed to be present in increased proportions in oxidized PrP106-126, could play a role in the pathogenesis of TSE and III) that the number of methionine residues in the PrP106-126 peptide seems to have a pivotal role in determining the physical and biological properties of PrP106-126.


Asunto(s)
Fragmentos de Péptidos/química , Fragmentos de Péptidos/toxicidad , Priones/química , Priones/toxicidad , Amiloide/ultraestructura , Animales , Bovinos , Supervivencia Celular/efectos de los fármacos , Humanos , Masculino , Metionina/química , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neurotoxinas/farmacología , Oxidación-Reducción , Fragmentos de Péptidos/ultraestructura , Priones/ultraestructura
14.
Med Sci (Paris) ; 34(5): 417-423, 2018 May.
Artículo en Francés | MEDLINE | ID: mdl-29900844

RESUMEN

Adiponectin (ApN) is a hormone produced by adipose tissue, yet the plasma level of ApN is decreased in overweight and obese people, as well as in people with diabetes. In the periphery, this decrease in circulating levels of ApN induces the establishment of a chronic low-grade inflammatory state and is involved in the development of insulin resistance and atheromas. Conversely, "favorable" living conditions, weight loss and regular physical exercise increase ApN blood concentration. Some forms of ApN can reach the brain parenchyma through the cerebrospinal fluid. In the brain, the increase in ApN exerts powerful antidepressant and anxiolytic effects, in particular by fighting against neuroinflammation.


Asunto(s)
Adiponectina/farmacología , Antiinflamatorios/farmacología , Antidepresivos/farmacología , Adiponectina/genética , Adiponectina/metabolismo , Tejido Adiposo/metabolismo , Animales , Antiinflamatorios/metabolismo , Antidepresivos/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiología , Humanos , Obesidad/etiología , Obesidad/psicología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética
15.
Transl Psychiatry ; 8(1): 159, 2018 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-30115912

RESUMEN

Major depression is a psychiatric disorder with complex etiology. About 30% of depressive patients are resistant to antidepressants that are currently available, likely because they only target the monoaminergic systems. Thus, identification of novel antidepressants with a larger action spectrum is urgently required. Epidemiological data indicate high comorbidity between metabolic and psychiatric disorders, particularly obesity and depression. We used a well-characterized anxiety/depressive-like mouse model consisting of continuous input of corticosterone for seven consecutive weeks. A panel of reliable behavioral tests were conducted to assessing numerous facets of the depression-like state, including anxiety, resignation, reduced motivation, loss of pleasure, and social withdrawal. Furthermore, metabolic features including weight, adiposity, and plasma biological parameters (lipids, adipokines, and cytokines) were investigated in corticosterone-treated mice. Our data show that chronic administration of corticosterone induced the parallel onset of metabolic and behavioral dysfunctions in mice. AdipoRon, a potent adiponectin receptor agonist, prevented the corticosterone-induced early onset of moderate obesity and metabolic syndromes. Moreover, in all the behavioral tests, daily treatment with AdipoRon successfully reversed the corticosterone-induced depression-like state in mice. AdipoRon exerted its pleiotropic actions on various systems including hippocampal neurogenesis, serotonergic neurotransmission, neuroinflammation, and the tryptophan metabolic pathway, which can explain its antidepressant properties. Our study highlights the pivotal role of the adiponergic system in the development of both metabolic and psychiatric disorders. AdipoRon may constitute a promising novel antidepressant.


Asunto(s)
Antidepresivos/farmacología , Ansiedad/tratamiento farmacológico , Depresión/tratamiento farmacológico , Piperidinas/farmacología , Receptores de Adiponectina/agonistas , Animales , Ansiedad/inducido químicamente , Conducta Animal/efectos de los fármacos , Corticosterona/efectos adversos , Citocinas/sangre , Depresión/inducido químicamente , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
16.
Artículo en Inglés | MEDLINE | ID: mdl-29950983

RESUMEN

Living in an enriched environment (EE) benefits health by acting synergistically on various biological systems including the immune and the central nervous systems. The dialog between the brain and the immune cells has recently gained interest and is thought to play a pivotal role in beneficial effects of EE. Recent studies show that T lymphocytes have an important role in hippocampal plasticity, learning, and memory, although the precise mechanisms by which they act on the brain remain elusive. Using a mouse model of EE, we show here that CD4+ T cells are essential for spinogenesis and glutamatergic synaptic function in the CA of the hippocampus. However, CD4+ lymphocytes do not influence EE-induced neurogenesis in the DG of the hippocampus, by contrast to what we previously demonstrated for CD8+ T cells. Importantly, CD4+ T cells located in the choroid plexus have a specific transcriptomic signature as a function of the living environment. Our study highlights the contribution of CD4+ T cells in the brain plasticity and function.

17.
Front Cell Neurosci ; 11: 352, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29184485

RESUMEN

We recently reported that increased levels of Adiponectin (ApN) in the brain led to microglia phenotype and activation state regulation, thus reducing both global brain inflammation and depressive-like behaviors in mice. Apart from this, little is known on ApN molecular effects on microglia, although these cells are crucial in both physiological and pathological processes. Here we fill this gap by studying the effects and targets of ApN toward neuroinflammation. Our findings suggest that ApN deficiency in mice leads to a higher sensitivity of mice to neuroinflammation that is due to enhanced microglia responsiveness to a pro-inflammatory challenge. Moreover, we show that globular ApN (gApN) exerts direct in vivo anti-inflammatory actions on microglia by reducing IL-1ß, IL-6, and TNFα synthesis. In vitro, gApN anti-inflammatory properties are confirmed in brain-sorted microglia, primary cultured and microglia cell line (BV2), but are not observed on astrocytes. Our results also show that gApN blocks LPS-induced nitrosative and oxidative stress in microglia. Finally, we demonstrate for the first time that these anti-inflammatory and anti-oxidant actions of gApN on microglia are mediated through an AdipoR1/NF-κB signaling pathway.

18.
Neuropharmacology ; 110(Pt A): 69-81, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27060411

RESUMEN

Thyrotropin Releasing Hormone (TRH) is a tripeptide that induces the release of Thyroid Stimulating Hormone (TSH) in the blood. Besides its role in the thyroid system, TRH has been shown to regulate several neuronal systems in the brain however its role in hippocampus remains controversial. Using electrophysiological recordings in acute mouse brain slices, we show that TRH depresses glutamate responses at the CA3-CA1 synapse through an action on NMDA receptors, which, as a consequence, decreases the ability of the synapse to establish a long term potentiation (LTP). TRH also induces a late increase in AMPA/kainate responses. Together, these results suggest that TRH plays an important role in the modulation of hippocampal neuronal activities, and they contribute to a better understanding of the mechanisms by which TRH impacts synaptic function underlying emotional states, learning and memory processes.


Asunto(s)
Región CA1 Hipocampal/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Ácido Glutámico/fisiología , Neuronas/fisiología , Hormona Liberadora de Tirotropina/farmacología , 2-Amino-5-fosfonovalerato/farmacología , Animales , Región CA1 Hipocampal/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Técnicas de Cultivo de Órganos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/fisiología
19.
J Neurosci ; 24(3): 620-7, 2004 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-14736847

RESUMEN

The accumulation and activation of microglial cells at sites of amyloid prion deposits or plaques have been documented extensively. Here, we investigate the in vivo recruitment of microglial cells soon after intraocular injection of scrapie-infected cell homogenate (hgtsc+) using immunohistochemistry on retinal sections. A population of CD11b/CD45-positive microglia was specifically detected within the ganglion and internal plexiform retinal cell layers by 2 d after intravitreal injection of hgtsc+. Whereas no chemotactism properties were ascribed to hgtsc+ alone, a massive migration of microglial cells was observed by incubating primary cultured neurons and astrocytes with hgtsc+ in a time- and concentration-dependent manner. hgtsc+ triggered the recruitment of microglial cells by interacting with both neurons and astrocytes by upregulation of the expression levels of a broad spectrum of neuronal and glial chemokines. We show that, in vitro and in vivo, the microglia migration is at least partly under the control of chemokine receptor-5 (CCR-5) activation, because highly specific CCR-5 antagonist TAK-779 significantly reduced the migration rate of microglia. Activated microglia recruited in the vicinity of prion may, in turn, cause neuronal cell damage by inducing apoptosis. These findings provide insight into the understanding of the cell-cell communication that takes place during the development of prion diseases.


Asunto(s)
Astrocitos/metabolismo , Microglía/fisiología , Neuronas/metabolismo , Proteínas PrPSc/farmacología , Enfermedades por Prión/fisiopatología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/patología , Recuento de Células , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Quimiocinas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Endopeptidasa K/química , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/patología , Neuroblastoma , Neuronas/efectos de los fármacos , Neuronas/patología , Nitritos/metabolismo , Nervio Óptico/patología , Proteínas PrPSc/patogenicidad , Enfermedades por Prión/metabolismo , Enfermedades por Prión/patología , Receptores CCR5/metabolismo , Retina/efectos de los fármacos , Retina/patología , Fracciones Subcelulares/química
20.
J Neurosci ; 23(2): 462-9, 2003 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-12533606

RESUMEN

We recently demonstrated that the 118-135 putative transmembrane domain of prion protein (PrP) exhibited membrane fusogenic properties and induced apoptotic neuronal cell death of rat cortical neurons, independently of its aggregation state. The aim of the present study was to analyze the in vivo neurotoxicity of the prion fragment P118-135 and to evaluate the potential role of the physiological isoform of PrP in the P118-135-induced cell death. Here, we demonstrate that the nonfibrillar P118-135 is cytotoxic to retinal neurons in vivo as monitored by intravitreal inoculation and recording of the electrical activity of retina and tissue examination. Moreover, knock-out PrP gene mice exhibit similar sensitivity to the nonfibrillar P118-135-induced cell death and electrical perturbations, strongly suggesting that cell death occurs independently of PrP expression. Interestingly, a variant nonfusogenic P118-135 peptide (termed P118-135theta) had no effects on in vivo neuronal viability, suggesting that the P118-135-induced cell death is mediated by its membrane destabilizing properties. These data have further been confirmed in vitro. We show that the fusogenic peptide P118-135 induces death of cultured neurons from both wild-type and knock-out PrP gene mice via an apoptotic-mediated pathway, involving early caspase activation and DNA fragmentation. Altogether these results emphasize the neurotoxicity of the fusogenic nonfibrillar PrP transmembrane domain and indicate that fibril formation and PrP expression are not obligatory requirements for neuronal cell death. The use of synthetic prion peptides could provide insights into the understanding of neuronal loss mechanisms that take place during the development of the various types of spongiform encephalopathies.


Asunto(s)
Fragmentos de Péptidos/toxicidad , Priones/biosíntesis , Priones/toxicidad , Animales , Apoptosis , Caspasas/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/citología , Corteza Cerebral/efectos de los fármacos , Fragmentación del ADN , Vías de Administración de Medicamentos , Electrorretinografía/efectos de los fármacos , Humanos , Etiquetado Corte-Fin in Situ , Técnicas In Vitro , Fusión de Membrana/fisiología , Ratones , Ratones Noqueados , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/enzimología , Fragmentos de Péptidos/administración & dosificación , Enfermedades por Prión/etiología , Priones/administración & dosificación , Priones/genética , Isoformas de Proteínas/fisiología , Estructura Terciaria de Proteína/fisiología , Retina/citología , Retina/efectos de los fármacos
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