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1.
Glia ; 70(1): 89-105, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34487590

RESUMEN

Microglia, the brain's resident macrophages, actively contribute to the homeostasis of cerebral parenchyma by sensing neuronal activity and supporting synaptic remodeling and plasticity. While several studies demonstrated different roles for astrocytes in sleep, the contribution of microglia in the regulation of sleep/wake cycle and in the modulation of synaptic activity in the different day phases has not been deeply investigated. Using light as a zeitgeber cue, we studied the effects of microglial depletion with the colony stimulating factor-1 receptor antagonist PLX5622 on the sleep/wake cycle and on hippocampal synaptic transmission in male mice. Our data demonstrate that almost complete microglial depletion increases the duration of NREM sleep and reduces the hippocampal excitatory neurotransmission. The fractalkine receptor CX3CR1 plays a relevant role in these effects, because cx3cr1GFP/GFP mice recapitulate what found in PLX5622-treated mice. Furthermore, during the light phase, microglia express lower levels of cx3cr1 and a reduction of cx3cr1 expression is also observed when cultured microglial cells are stimulated by ATP, a purinergic molecule released during sleep. Our findings suggest that microglia participate in the regulation of sleep, adapting their cx3cr1 expression in response to the light/dark phase, and modulating synaptic activity in a phase-dependent manner.


Asunto(s)
Microglía , Transmisión Sináptica , Animales , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/metabolismo , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Neuronas/metabolismo , Sueño
2.
FASEB J ; 33(12): 14204-14220, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31665922

RESUMEN

Polymorphic variants of the gene encoding for metabotropic glutamate receptor 3 (mGlu3) are linked to schizophrenia. Because abnormalities of cortical GABAergic interneurons lie at the core of the pathophysiology of schizophrenia, we examined whether mGlu3 receptors influence the developmental trajectory of cortical GABAergic transmission in the postnatal life. mGlu3-/- mice showed robust changes in the expression of interneuron-related genes in the prefrontal cortex (PFC), including large reductions in the expression of parvalbumin (PV) and the GluN1 subunit of NMDA receptors. The number of cortical cells enwrapped by perineuronal nets was increased in mGlu3-/- mice, suggesting that mGlu3 receptors shape the temporal window of plasticity of PV+ interneurons. Electrophysiological measurements of GABAA receptor-mediated responses revealed a more depolarized reversal potential of GABA currents in the somata of PFC pyramidal neurons in mGlu3-/- mice at postnatal d 9 associated with a reduced expression of the K+/Cl- symporter. Finally, adult mGlu3-/- mice showed lower power in electroencephalographic rhythms at 1-45 Hz in quiet wakefulness as compared with their wild-type counterparts. These findings suggest that mGlu3 receptors have a strong impact on the development of cortical GABAergic transmission and cortical neural synchronization mechanisms corroborating the concept that genetic variants of mGlu3 receptors may predispose to psychiatric disorders.-Imbriglio, T., Verhaeghe, R., Martinello, K., Pascarelli, M. T., Chece, G., Bucci, D., Notartomaso, S., Quattromani, M., Mascio, G., Scalabrì, F., Simeone, A., Maccari, S., Del Percio, C., Wieloch, T., Fucile, S., Babiloni, C., Battaglia, G., Limatola, C., Nicoletti, F., Cannella, M. Developmental abnormalities in cortical GABAergic system in mice lacking mGlu3 metabotropic glutamate receptors.


Asunto(s)
Corteza Cerebral/anomalías , Embrión de Mamíferos/anomalías , Neuronas GABAérgicas/fisiología , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Biomarcadores , Corteza Cerebral/metabolismo , Femenino , Regulación de la Expresión Génica , Genes Homeobox , Inmunohistoquímica , Masculino , Ratones , Ratones Noqueados , ARN Mensajero , Receptores de Glutamato Metabotrópico/genética
3.
J Neurosci ; 37(14): 3926-3939, 2017 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-28292827

RESUMEN

Oleandrin is a glycoside that inhibits the ubiquitous enzyme Na+/K+-ATPase. In addition to its known effects on cardiac muscle, recent in vitro and in vivo evidence highlighted its potential for anticancer properties. Here, we evaluated for the first time the effect of oleandrin on brain tumors. To this aim, mice were transplanted with human or murine glioma and analyzed for tumor progression upon oleandrin treatment. In both systems, oleandrin impaired glioma development, reduced tumor size, and inhibited cell proliferation. We demonstrated that oleandrin does the following: (1) enhances the brain-derived neurotrophic factor (BDNF) level in the brain; (2) reduces both microglia/macrophage infiltration and CD68 immunoreactivity in the tumor mass; (3) decreases astrogliosis in peritumoral area; and (4) reduces glioma cell infiltration in healthy parenchyma. In BDNF-deficient mice (bdnftm1Jae/J) and in glioma cells silenced for TrkB receptor expression, oleandrin was not effective, indicating a crucial role for BDNF in oleandrin's protective and antitumor functions. In addition, we found that oleandrin increases survival of temozolomide-treated mice. These results encourage the development of oleandrin as possible coadjuvant agent in clinical trials of glioma treatment.SIGNIFICANCE STATEMENT In this work, we paved the road for a new therapeutic approach for the treatment of brain tumors, demonstrating the potential of using the cardioactive glycoside oleandrin as a coadjuvant drug to standard chemotherapeutics such as temozolomide. In murine models of glioma, we demonstrated that oleandrin significantly increased mouse survival and reduced tumor growth both directly on tumor cells and indirectly by promoting an antitumor brain microenvironment with a key protective role played by the neurotrophin brain-derived neurotrophic factor.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Cardenólidos/uso terapéutico , Glicósidos Cardíacos/uso terapéutico , Glioma/tratamiento farmacológico , Carga Tumoral/efectos de los fármacos , Animales , Neoplasias Encefálicas/patología , Cardenólidos/farmacología , Glicósidos Cardíacos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Glioma/patología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Ratones Transgénicos , Carga Tumoral/fisiología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
4.
J Neuroinflammation ; 10: 108, 2013 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-23981568

RESUMEN

BACKGROUND: N-Methyl-D-aspartate receptors (NMDARs) play fundamental roles in basic brain functions such as excitatory neurotransmission and learning and memory processes. Their function is largely regulated by factors released by glial cells, including the coagonist d-serine. We investigated whether the activation of microglial CX3CR1 induces the release of factors that modulate NMDAR functions. METHODS: We recorded the NMDAR component of the field excitatory postsynaptic potentials (NMDA-fEPSPs) elicited in the CA1 stratum radiatum of mouse hippocampal slices by Shaffer collateral stimulation and evaluated D-serine content in the extracellular medium of glial primary cultures by mass spectrometry analysis. RESULTS: We demonstrated that CX3CL1 increases NMDA-fEPSPs by a mechanism involving the activity of the adenosine receptor type A2 (A2AR) and the release of the NMDAR coagonist D-serine. Specifically (1) the selective A2AR blocker 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261) and the genetic ablation of A2AR prevent CX3CL1 action while the A2AR agonist 5-(6-amino-2-(phenethylthio)-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydrofuran-2-carboxamide (VT7) mimics CX3CL1 effect, and (2) the selective blocking of the NMDAR glycine (and D-serine) site by 5,7-dicholorokynurenic acid (DCKA), the enzymatic degradation of D-serine by D-amino acid oxidase (DAAO) and the saturation of the coagonist site by D-serine, all block the CX3CL1 effect. In addition, mass spectrometry analysis demonstrates that stimulation of microglia and astrocytes with CX3CL1 or VT7 increases D-serine release in the extracellular medium. CONCLUSIONS: CX3CL1 transiently potentiates NMDAR function though mechanisms involving A2AR activity and the release of D-serine.


Asunto(s)
Quimiocina CX3CL1/metabolismo , Hipocampo/metabolismo , Receptores de Adenosina A2/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Serina/metabolismo , Animales , Cromatografía Liquida , Potenciales Postsinápticos Excitadores/fisiología , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Neuroglía/metabolismo , Técnicas de Cultivo de Órganos , Técnicas de Placa-Clamp
5.
J Neurosci ; 31(45): 16327-35, 2011 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-22072684

RESUMEN

The chemokine CX3CL1 and its receptor CX3CR1 are constitutively expressed in the nervous system. In this study, we used in vivo murine models of permanent middle cerebral artery occlusion (pMCAO) to investigate the protective potential of CX3CL1. We report that exogenous CX3CL1 reduced ischemia-induced cerebral infarct size, neurological deficits, and caspase-3 activation. CX3CL1-induced neuroprotective effects were long lasting, being observed up to 50 d after pMCAO in rats. The neuroprotective action of CX3CL1 in different models of brain injuries is mediated by its inhibitory activity on microglia and, in vitro, requires the activation of adenosine receptor 1 (A1R). We show that, in the presence of the A1R antagonist 1,3-dipropyl-8-cyclopentylxanthine and in A1R⁻/⁻ mice, the neuroprotective effect of CX3CL1 on pMCAO was abolished, indicating the critical importance of the adenosine system in CX3CL1 protection also in vivo. In apparent contrast with the above reported data but in agreement with previous findings, cx3cl1⁻/⁻ and cx3cr1(GFP/GFP) mice, respectively, deficient in CX3CL1 or CX3CR1, had less severe brain injury on pMCAO, and the administration of exogenous CX3CL1 increased brain damage in cx3cl1⁻/⁻ ischemic mice. We also report that CX3CL1 induced a different phagocytic activity in wild type and cx3cl1⁻/⁻ microglia in vitro during cotreatment with the medium conditioned by neurons damaged by oxygen-glucose deprivation. Together, these data suggest that acute administration of CX3CL1 reduces ischemic damage via an adenosine-dependent mechanism and that the absence of constitutive CX3CL1-CX3CR1 signaling changes the outcome of microglia-mediated effects during CX3CL1 administration to ischemic brain.


Asunto(s)
Quimiocina CX3CL1/metabolismo , Quimiocina CX3CL1/uso terapéutico , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/prevención & control , Antagonistas del Receptor de Adenosina A1/uso terapéutico , Análisis de Varianza , Animales , Animales Modificados Genéticamente , Animales Recién Nacidos , Infarto Encefálico/etiología , Infarto Encefálico/prevención & control , Receptor 1 de Quimiocinas CX3C , Células Cultivadas , Corteza Cerebral/citología , Quimiocina CX3CL1/deficiencia , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática/métodos , Glucosa/deficiencia , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Hipoxia/prevención & control , Infarto de la Arteria Cerebral Media/complicaciones , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/terapia , Neuronas/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Ratas , Receptores de Quimiocina/deficiencia , Receptores Purinérgicos P1/deficiencia , Xantinas/uso terapéutico
6.
Br J Pharmacol ; 178(24): 4891-4906, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34411281

RESUMEN

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) patients exhibit dysfunctional energy metabolism and weight loss, which is negatively correlated with survival, together with neuroinflammation. However, the possible contribution of neuroinflammation to deregulations of feeding behaviour in ALS has not been studied in detail. We here investigated if microglial KCa 3.1 is linked to hypothalamic neuroinflammation and affects feeding behaviours in ALS mouse models. EXPERIMENTAL APPROACH: hSOD1G93A and TDP43A315T mice were treated daily with 120 mg·kg-1 of TRAM-34 or vehicle by intraperitoneal injection from the presymptomatic until the disease onset phase. Body weight and food intake were measured weekly. The later by weighing food provided minus that left in the cage. RT-PCR and immunofluorescence analysis were used to characterize microglia phenotype and the main populations of melanocortin neurons in the hypothalamus of hSOD1G93A and age-matched non-tg mice. The cannabinoid-opioid interactions in feeding behaviour of hSOD1G93A mice were studied using an inverse agonist and an antagonist of the cannabinoid receptor CB1 (rimonabant) and µ-opioid receptors (naloxone), respectively. KEY RESULTS: We found that treatment of hSOD1G93A mice with the KCa 3.1 inhibitor TRAM-34 (i), attenuates the pro-inflammatory phenotype of hypothalamic microglia, (ii) increases food intake and promotes weight gain, (iii) increases the number of healthy pro-opiomelanocortin (POMC) neurons and (iv), changes the expression of cannabinoid receptors involved in energy homeostasis. CONCLUSION AND IMPLICATIONS: Using ALS mouse models, we describe defects in the hypothalamic melanocortin system that affect appetite control. These results reveal a new regulatory role for KCa 3.1 to counteract weight loss in ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral , Conducta Alimentaria , Canales de Potasio Calcio-Activados/metabolismo , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Modelos Animales de Enfermedad , Metabolismo Energético , Homeostasis , Melanocortinas , Ratones , Ratones Transgénicos , Microglía/citología , Pirazoles/farmacología , Receptores de Cannabinoides , Médula Espinal/metabolismo , Superóxido Dismutasa-1/metabolismo , Aumento de Peso
7.
Front Cell Neurosci ; 13: 414, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31607865

RESUMEN

In the CNS, the chemokine CX3CL1 (fractalkine) is expressed on neurons while its specific receptor CX3CR1 is expressed on microglia and macrophages. Microglia play an important role in health and disease through CX3CL1/CX3CR1 signaling, and in many neurodegenerative disorders, microglia dysregulation has been associated with neuro-inflammation. We have previously shown that CX3CL1 has neuroprotective effects against cerebral ischemia injury. Here, we investigated the involvement of CX3CL1 in the modulation of microglia phenotype and the underlying neuroprotective effect on ischemia injury. The expression profiles of anti- and pro-inflammatory genes showed that CX3CL1 markedly inhibited microglial activation both in vitro and in vivo after permanent middle cerebral artery occlusion (pMCAO), accompanied by an increase in the expression of anti-inflammatory genes. Moreover, CX3CL1 induces a metabolic switch in microglial cells with an increase in the expression of genes related to the oxidative pathway and a reduction in those related to the glycolytic pathway, which is the metabolic state associated to the pro-inflammatory phenotype for energy production. The data reported in this paper suggest that CX3CL1 protects against cerebral ischemia modulating the activation state of microglia and its metabolism in order to restrain inflammation and organize a neuroprotective response against the ischemic insult.

8.
Front Cell Neurosci ; 13: 41, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30853898

RESUMEN

Extracellular-released vesicles (EVs), such as microvesicles (MV) and exosomes (Exo) provide a new type of inter-cellular communication, directly transferring a ready to use box of information, consisting of proteins, lipids and nucleic acids. In the nervous system, EVs participate to neuron-glial cross-talk, a bidirectional communication important to preserve brain homeostasis and, when dysfunctional, involved in several CNS diseases. We investigated whether microglia-derived EVs could be used to transfer a protective phenotype to dysfunctional microglia in the context of a brain tumor. When MV, isolated from microglia stimulated with LPS/IFNγ were brain injected in glioma-bearing mice, we observed a phenotype switch of tumor associated myeloid cells (TAMs) and a reduction of tumor size. Our findings indicate that the MV cargo, which contains upregulated transcripts for several inflammation-related genes, can transfer information in the brain of glioma bearing mice modifying microglial gene expression, reducing neuronal death and glioma invasion, thus promoting the recovery of brain homeostasis.

9.
Elife ; 62017 12 29.
Artículo en Inglés | MEDLINE | ID: mdl-29286001

RESUMEN

In glioma, microglia and infiltrating macrophages are exposed to factors that force them to produce cytokines and chemokines, which contribute to tumor growth and to maintaining a pro-tumorigenic, immunosuppressed microenvironment. We demonstrate that housing glioma-bearing mice in enriched environment (EE) reverts the immunosuppressive phenotype of infiltrating myeloid cells, by modulating inflammatory gene expression. Under these conditions, the branching and patrolling activity of myeloid cells is increased, and their phagocytic activity is promoted. Modulation of gene expression depends on interferon-(IFN)-γ produced by natural killer (NK) cells. This modulation disappears in mice depleted of NK cells or lacking IFN-γ, and was mimicked by exogenous interleukin-15 (IL-15). Further, we describe a key role for brain-derived neurotrophic factor (BDNF) that is produced in the brain of mice housed in EE, in mediating the expression of IL-15 in CD11b+ cells. These data define novel mechanisms linking environmental cues to the acquisition of a pro-inflammatory, anti-tumor microenvironment in mouse brain.


Asunto(s)
Plasticidad de la Célula , Glioma/fisiopatología , Microglía/fisiología , Microambiente Tumoral , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Tolerancia Inmunológica , Células Asesinas Naturales/fisiología , Macrófagos/fisiología , Ratones
10.
Oncotarget ; 7(21): 30781-96, 2016 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-27096953

RESUMEN

Malignant gliomas are among the most frequent and aggressive cerebral tumors, characterized by high proliferative and invasive indexes. Standard therapy for patients, after surgery and radiotherapy, consists of temozolomide (TMZ), a methylating agent that blocks tumor cell proliferation. Currently, there are no therapies aimed at reducing tumor cell invasion. Ion channels are candidate molecular targets involved in glioma cell migration and infiltration into the brain parenchyma. In this paper we demonstrate that: i) blockade of the calcium-activated potassium channel KCa3.1 with TRAM-34 has co-adjuvant effects with TMZ, reducing GL261 glioma cell migration, invasion and colony forming activity, increasing apoptosis, and forcing cells to pass the G2/M cell cycle phase, likely through cdc2 de-phosphorylation; ii) KCa3.1 silencing potentiates the inhibitory effect of TMZ on glioma cell viability; iii) the combination of TMZ/TRAM-34 attenuates the toxic effects of glioma conditioned medium on neuronal cultures, through a microglia dependent mechanism since the effect is abolished by clodronate-induced microglia killing; iv) TMZ/TRAM-34 co-treatment increases the number of apoptotic tumor cells, and the mean survival time in a syngeneic mouse glioma model (C57BL6 mice implanted with GL261 cells); v) TMZ/TRAM-34 co-treatment reduces cell viability of GBM cells and cancer stem cells (CSC) freshly isolated from patients.Taken together, these data suggest a new therapeutic approach for malignant glioma, targeting both glioma cell proliferating and migration, and demonstrate that TMZ/TRAM-34 co-treatment affects both glioma cells and infiltrating microglia, resulting in an overall reduction of tumor cell progression.


Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Dacarbazina/análogos & derivados , Glioma/tratamiento farmacológico , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/antagonistas & inhibidores , Pirazoles/farmacología , Animales , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/mortalidad , Proteína Quinasa CDC2/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dacarbazina/farmacología , Dacarbazina/uso terapéutico , Sinergismo Farmacológico , Quimioterapia Combinada , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Glioma/mortalidad , Humanos , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/genética , Estimación de Kaplan-Meier , Ratones , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/mortalidad , Células Madre Neoplásicas/efectos de los fármacos , Fosforilación , Cultivo Primario de Células , Pirazoles/uso terapéutico , Temozolomida
11.
Nat Commun ; 6: 6623, 2015 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-25818172

RESUMEN

Mice exposed to standard (SE) or enriched environment (EE) were transplanted with murine or human glioma cells and differences in tumour development were evaluated. We report that EE exposure affects: (i) tumour size, increasing mice survival; (ii) glioma establishment, proliferation and invasion; (iii) microglia/macrophage (M/Mφ) activation; (iv) natural killer (NK) cell infiltration and activation; and (v) cerebral levels of IL-15 and BDNF. Direct infusion of IL-15 or BDNF in the brain of mice transplanted with glioma significantly reduces tumour growth. We demonstrate that brain infusion of IL-15 increases the frequency of NK cell infiltrating the tumour and that NK cell depletion reduces the efficacy of EE and IL-15 on tumour size and of EE on mice survival. BDNF infusion reduces M/Mφ infiltration and CD68 immunoreactivity in tumour mass and reduces glioma migration inhibiting the small G protein RhoA through the truncated TrkB.T1 receptor. These results suggest alternative approaches for glioma treatment.


Asunto(s)
Ambiente , Glioma/patología , Células Asesinas Naturales/inmunología , Macrófagos/inmunología , Microglía/inmunología , Juego e Implementos de Juego , Animales , Antígenos CD/efectos de los fármacos , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/efectos de los fármacos , Antígenos de Diferenciación Mielomonocítica/metabolismo , Factor Neurotrófico Derivado del Encéfalo/inmunología , Factor Neurotrófico Derivado del Encéfalo/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Glioma/inmunología , Glioma/mortalidad , Humanos , Interleucina-15/inmunología , Interleucina-15/farmacología , Activación de Macrófagos , Macrófagos/efectos de los fármacos , Ratones , Microglía/efectos de los fármacos , Invasividad Neoplásica , Trasplante de Neoplasias , Estimulación Física , Receptor trkB/efectos de los fármacos , Receptor trkB/metabolismo , Medio Social , Tasa de Supervivencia , Carga Tumoral/efectos de los fármacos , Proteínas de Unión al GTP rho/efectos de los fármacos , Proteínas de Unión al GTP rho/metabolismo , Proteína de Unión al GTP rhoA
12.
Front Cell Neurosci ; 8: 472, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25653593

RESUMEN

Neuronal death induced by overactivation of N-methyl-d-aspartate receptors (NMDARs) is implicated in the pathophysiology of many neurodegenerative diseases such as stroke, epilepsy and traumatic brain injury. This toxic effect is mainly mediated by NR2B-containing extrasynaptic NMDARs, while NR2A-containing synaptic NMDARs contribute to cell survival, suggesting the possibility of therapeutic approaches targeting specific receptor subunits. We report that fractalkine/CX3CL1 protects hippocampal neurons from NMDA-induced cell death with a mechanism requiring the adenosine receptors type 2A (A2AR). This is different from CX3CL1-induced protection from glutamate (Glu)-induced cell death, that fully depends on A1R and requires in part A3R. We show that CX3CL1 neuroprotection against NMDA excitotoxicity involves D-serine, a co-agonist of NR2A/NMDAR, resulting in cyclic AMP-dependent transcription factor cyclic-AMP response element-binding protein (CREB) phosphorylation.

13.
Front Cell Neurosci ; 8: 193, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25071451

RESUMEN

Upon noxious insults, cells of the brain parenchyma activate endogenous self-protective mechanisms to counteract brain damage. Interplay between microglia and astrocytes can be determinant to build a physiological response to noxious stimuli arisen from injury or stress, thus understanding the cross talk between microglia and astrocytes would be helpful to elucidate the role of glial cells in endogenous protective mechanisms and might contribute to the development of new strategy to mobilize such program and reduce brain cell death. Here we demonstrate that chemokines CX3CL1 and CXCL16 are molecular players that synergistically drive cross-talk between neurons, microglia and astrocytes to promote physiological neuroprotective mechanisms that counteract neuronal cell death due to ischemic and excitotoxic insults. In an in vivo model of permanent middle cerebral artery occlusion (pMCAO) we found that exogenous administration of soluble CXCL16 reduces ischemic volume and that, upon pMCAO, endogenous CXCL16 signaling restrains brain damage, being ischemic volume reduced in mice that lack CXCL16 receptor. We demonstrated that CX3CL1, acting on microglia, elicits CXCL16 release from glia and this is important to induce neroprotection since lack of CXCL16 signaling impairs CX3CL1 neuroprotection against both in vitro Glu-excitotoxic insult and pMCAO. Moreover the activity of adenosine receptor A3R and the astrocytic release of CCL2 play also a role in trasmembrane chemokine neuroprotective effect, since their inactivation reduces CX3CL1- and CXCL16 induced neuroprotection.

14.
J Neuroimmunol ; 263(1-2): 75-82, 2013 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-23968561

RESUMEN

In this paper we show for the first time that: i) astrocytes are required for the neuroprotective activity of CX3CL1 against excitotoxicity; ii) inhibition of the glutamate transporter 1 (GLT-1) prejudices CX3CL1-mediated neuroprotection; iii) CX3CL1 increases GLT-1 activity on astrocytes. The modulation of GLT-1 activity induced by CX3CL1 on astrocytes requires the presence and the activity of A1 adenosine receptor (A1R), being blocked by the specific antagonist DPCPX and absent in A1R(-/-) astrocytes. These data introduce the astrocytes as active players in CX3CL1-mediated signaling between microglia and neurons, identifying GLT-1 as a key mediator of the neuroprotective activity of CX3CL1.


Asunto(s)
Quimiocina CX3CL1/fisiología , Transportador 2 de Aminoácidos Excitadores/antagonistas & inhibidores , Neuronas/inmunología , Neuronas/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Regulación hacia Arriba/inmunología , Animales , Animales Recién Nacidos , Supervivencia Celular/inmunología , Células Cultivadas , Técnicas de Cocultivo , Transportador 2 de Aminoácidos Excitadores/toxicidad , Glucosa/toxicidad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/citología , Ratas , Ratas Wistar
15.
Neuropsychopharmacology ; 35(7): 1550-9, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20200508

RESUMEN

Fractalkine/CX3CL1 is a neuron-associated chemokine, which modulates microglia-induced neurotoxicity activating the specific and unique receptor CX3CR1. CX3CL1/CX3CR1 interaction modulates the release of cytokines from microglia, reducing the level of tumor necrosis factor-alpha, interleukin-1-beta, and nitric oxide and induces the production of neurotrophic substances, both in vivo and in vitro. We have recently shown that blocking adenosine A(1) receptors (A(1)R) with the specific antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) abolishes CX3CL1-mediated rescue of neuronal excitotoxic death and that CX3CL1 induces the release of adenosine from microglia. In this study, we show that the presence of extracellular adenosine is mandatory for the neurotrophic effect of CX3CL1 as reducing adenosine levels in hippocampal cultures, by adenosine deaminase treatment, strongly impairs CX3CL1-mediated neuroprotection. Furthermore, we confirm the predominant role of microglia in mediating the neuronal effects of CX3CL1, because the selective depletion of microglia from hippocampal cultures treated with clodronate-filled liposomes causes the complete loss of effect of CX3CL1. We also show that hippocampal neurons obtained from A(1)R(-/-) mice are not protected by CX3CL1 whereas A(2A)R(-/-) neurons are. The requirement of functional A(1)R for neuroprotection is not unique for CX3CL1 as A(1)R(-/-) hippocampal neurons are not rescued from Glu-induced cell death by other neurotrophins such as brain-derived neurotrophic factor and erythropoietin, which are fully active on wt neurons.


Asunto(s)
Hipocampo/citología , Microglía/fisiología , Neuronas/efectos de los fármacos , Receptor de Adenosina A1/metabolismo , Receptores de Quimiocina/fisiología , Adenosina/farmacología , Antagonistas del Receptor de Adenosina A1 , Adenosina Desaminasa/farmacología , Adenosina Difosfato/análogos & derivados , Adenosina Difosfato/farmacología , Animales , Animales Recién Nacidos , Factor Neurotrófico Derivado del Encéfalo/farmacología , Receptor 1 de Quimiocinas CX3C , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Movimiento Celular/efectos de los fármacos , Ácido Clodrónico/farmacología , Eritropoyetina/farmacología , Ácido Glutámico/toxicidad , Proteínas Fluorescentes Verdes/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microglía/química , Técnicas de Cultivo de Órganos , Ratas , Receptor de Adenosina A1/deficiencia , Receptores de Adenosina A2/deficiencia , Receptores de Quimiocina/genética , Xantinas/farmacología
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