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Objective: To determine the discriminative capacity of myocardial perfusion with single photon emission tomography (SPECT) to predict coronary obstructions by coronary angiography. To determine mortality and major cardiovascular events at follow-up. Materials and methods: . Retrospective observational study with clinical follow-up in patients undergoing SPECT and then coronary angiography. We excluded patients with myocardial infarction and percutaneous and/or surgical revascularization in the previous 6 months. Results: 105 cases were included in the study. The most commonly used SPECT protocol was pharmacological (70%). Patients with perfusion defect ≥10% of total ventricular mass (TVM) had significant coronary lesions (SCL) in 88% of cases (sensitivity 87.5% and specificity 83%). On the other hand, having ischemia ≥10% of the TVM was associated with 80% SCL (sensitivity: 72%, specificity: 65%). Clinical follow-up at 48 months evidenced that a perfusion defect ≥ 10% was predictive of major cardiovascular events (MACE) in both univariate (HR=5.3; 95%CI 1.2 - 22.2; p=0.022) and multivariate (HR= 6.1; 95%CI 1.3 - 26.9; p= 0.017) analyses. Conclusions: . Having a perfusion defect ≥10% of the MVT in the SPECT study predicted with high probability and sensitivity the existence of SCL (>80%); moreover, this group had higher MACE at follow-up.
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This paper critically analyses the complexity of the land grabbing phenomenon in Argentina. We study land grabbing processes linked to the expansion of agribusiness by focusing on corporate regionally extended land grabbers' strategies through five dimensions: (1) forms of control over land (and other resources) are not restricted to the formal acquisition of property, (2) the role of both national and foreign actors are essential in land grabbing dynamics, (3) land grabbing is not expressed exclusively by the scale of the area traded, (4) the current cycle of land grabbing is part of the convergence of multiple crises and (5) forms of political action are complex and involve diverse positioning. We conclude that land grabbing mechanisms unfold differently depending on the diversity of socio-spatial formations they encounter in each territory and that forms of political action "from below" are complex and not restricted to overt conflict.
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Astrocytes play a key role by providing antioxidant support to nearby neurons under oxidative stress. We have previously demonstrated that in vitro astroglial subtype 3 metabotropic glutamate receptor (mGlu3R) is neuroprotective. However, its role during aging has been poorly explored. Our study aimed to determine whether LY379268, an mGlu3R agonist, exerts an antioxidant effect on aged cultured rat astrocytes. Aged cultured astrocytes obtained after 9-weeks (9w) in vitro were positive for ß-galactosidase stain, showed decreased mGlu3R and glutathione (GSH) levels and superoxide dismutase (SOD) activity, while nuclear erythroid factor 2 (Nrf2) protein levels, reactive oxygen species (ROS) production and apoptosis were increased. Treatment of 9w astrocytes with LY379268 resulted in an increase in mGlu3R and Nrf2 protein levels and SOD activity, and decreased mitochondrial ROS levels and apoptosis. mGlu3R activation in aged astrocytes also prevented hippocampal neuronal death induced by Aß1-42 in co-culture assays. We conclude that activation of mGlu3R in aged astrocytes had an anti-oxidant effect and protected hippocampal neurons against Aß-induced neurotoxicity. The present study suggests mGlu3R activation in aging astrocytes as a therapeutic strategy to slow down age-associated neurodegeneration.
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Antioxidantes/farmacología , Astrocitos/metabolismo , Senescencia Celular/fisiología , Fármacos Neuroprotectores/farmacología , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Aminoácidos/farmacología , Animales , Astrocitos/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Técnicas de Cocultivo , Femenino , Embarazo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The mechanics of ß-amyloid (Aß) clearance by astrocytes has not been univocally described, with different mediators appearing to contribute to this process under different conditions. Our laboratory has demonstrated neuroprotective effects of astroglial subtype 3 metabotropic glutamate receptor (mGlu3R), which are dependent on the secreted form of the amyloid precursor protein (sAPPα) as well as on Aß clearance; however, the mechanism underlying mGlu3R-induced Aß uptake by astrocytes remains unclear. The present study shows that conditioned medium from mGlu3R-stimulated astrocytes increased Aß uptake by naïve astrocytes through a mechanism dependent on sAPPα, since sAPPα depletion from conditioned medium inhibited Aß phagocytosis. Concordantly, recombinant sAPPα also increased Aß uptake. Since we show that both sAPPα and the mGlu3R agonist LY379268 increased expression of class-A scavenger receptor (SR-A) in astrocytes, we next determined whether SR-A mediates mGlu3R- or sAPPα-induced Aß uptake by using astrocyte cultures derived from SR-A knockout mice. We found that the effects of LY379268 as well as sAPPα on Aß uptake were abolished in SR-A-deficient astrocytes, indicating a major role for this scavenger receptor in LY379268- and sAPPα-stimulated Aß clearance by astrocytes. We also show results of coimmunoprecipitation and functional assays offering evidence of possible heterotrimerization of sAPPα with Aß and SR-A which could allow Aß to enter the astrocyte. In conclusion the present paper describes a novel pathway for Aß clearance by astrocytes involving sAPPα as an enhancer of SR-A-dependent Aß phagocytosis.
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Precursor de Proteína beta-Amiloide/metabolismo , Astrocitos/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Receptores Depuradores de Clase A/metabolismo , Aminoácidos/farmacología , Precursor de Proteína beta-Amiloide/genética , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Supervivencia Celular , Células Cultivadas , Medios de Cultivo Condicionados , Humanos , Ratones , Ratones Endogámicos ICR , Ratones Noqueados , Fagocitosis , Cultivo Primario de Células , Ratas Wistar , Receptores de Glutamato Metabotrópico/agonistas , Receptores Depuradores de Clase A/efectos de los fármacos , Receptores Depuradores de Clase A/genéticaRESUMEN
Recent findings relate obesity to inflammation in key hypothalamic areas for body weight control. Hypothalamic inflammation has also been related to oxidative stress. Palmitic acid (PA) is the most abundant free fatty acid found in food, and in vitro studies indicate that it triggers a pro-inflammatory response in the brain. Melanocortins are neuropeptides with proven anti-inflammatory and neuroprotective action mediated by melanocortin receptor 4 (MC4R), but little is known about the effect of melanocortins on oxidative stress. The aim of this study was to investigate whether melanocortins could alleviate oxidative stress induced by a high fat diet (HFD) model. We found that NDP-MSH treatment decreased PA-induced reactive oxygen species production in astrocytes, an effect blocked by the MC4R inhibitor JKC363. NDP-MSH abolished nuclear translocation of Nrf2 induced by PA and blocked the inhibitory effect of PA on superoxide dismutase (SOD) activity and glutathione levels while it also per se increased activity of SOD and γ-glutamate cysteine ligase (γ-GCL) antioxidant enzymes. However, HFD reduced hypothalamic MC4R and brain derived neurotrophic factor mRNA levels, thereby preventing the neuroprotective mechanism induced by melanocortins.
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Antiinflamatorios/administración & dosificación , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Encefalitis/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Obesidad/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ácido Palmítico/administración & dosificación , alfa-MSH/análogos & derivados , Animales , Dieta Alta en Grasa , Encefalitis/complicaciones , Encefalitis/prevención & control , Masculino , Obesidad/complicaciones , Cultivo Primario de Células , Ratas Endogámicas WKY , Ratas Wistar , Transducción de Señal , alfa-MSH/administración & dosificaciónRESUMEN
α-Melanocyte stimulating hormone (α-MSH) is a melanocortin which exerts potent anti-inflammatory and anti-apoptotic effects. Melanocortin 4 receptors (MC4R) are abundantly expressed in the brain and we previously demonstrated that [Nle(4), D-Phe(7)]melanocyte-stimulating hormone (NDP-MSH), an α-MSH analogue, increased expression of brain derived-neurotrophic factor (BDNF), and peroxisome proliferator-activated receptor-γ (PPAR-γ). We hypothesized that melanocortins could affect striatal cell survival through BDNF and PPAR-γ. First, we determined the expression of these factors in the striatum. Acute intraperitoneal administration (0.5â¯mg/kg) of α-MSH increased the levels of BDNF mRNA in rat striatum but not in rat cerebral cortex. Also, protein expression of PPAR-γ and MC4R was increased by acute treatment with α-MSH in striatum but not in cortex. No changes were observed by 48â¯h treatment. Next, we evaluated melanocortins effect on neuron and glial survival. 3-nitropropionic acid (3-NP), which is known to induce striatal degeneration, was used to induce cell death in the rat striatal cell line ST14A expressing mutant human huntingtin (Q120) or in ST14A cells expressing normal human huntingtin (Q15), in primary cultured astrocytes, and in BV2 cells. NDP-MSH protected Q15 cells, astrocytes and BV2 cells from death by 3-NP whereas it did not fully protect Q120 cells. Protection of Q15 cells and astrocytes was blocked by a MC4R specific inhibitor (JKC-363) and a PPAR-γ antagonist (GW9662). The BDNF receptor antagonist (ANA-12) abolished NDP-MSH protective effect in astrocytes but not in Q15 cells. We demonstrate for the first time that melanocortins, acting through PPAR-γ and BDNF, protect neurons and glial cells from 3-NP toxicity.
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Astrocitos/efectos de los fármacos , Neuroglía/efectos de los fármacos , Neuronas/efectos de los fármacos , Nitrocompuestos/farmacología , Propionatos/farmacología , Receptor de Melanocortina Tipo 4/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hormonas Estimuladoras de los Melanocitos/efectos de los fármacos , Ratas WistarRESUMEN
Astrocytes are glial cells that help maintain brain homeostasis and become reactive in neurodegenerative processes releasing both harmful and beneficial factors. We have demonstrated that brain-derived neurotrophic factor (BDNF) expression is induced by melanocortins in astrocytes but BDNF actions in astrocytes are largely unknown. We hypothesize that BDNF may prevent astrocyte death resulting in neuroprotection. We found that BDNF increased astrocyte viability, preventing apoptosis induced by serum deprivation by decreasing active caspase 3 and p53 expression. The anti-apoptotic action of BDNF was abolished by ANA-12 (a specific TrkB antagonist) and by K252a (a general Trk antagonist). Astrocytes only express the BDNF receptor TrkB-truncated isoform 1, TrkB-T1. BDNF induced ERK, Akt, and Src (a non-receptor tyrosine kinase) activation in astrocytes. Blocking ERK and Akt pathways abolished BDNF protection in serum deprivation-induced cell death. Moreover, BDNF protected astrocytes from death by 3-nitropropionic acid (3-NP), an effect also blocked by ANA-12, K252a, and inhibitors of ERK, calcium, and Src. BDNF reduced reactive oxygen species levels induced in astrocytes by 3-NP and increased xCT expression and glutathione levels. Astrocyte-conditioned medium (ACM) from untreated astrocytes partially protected PC12 neurons, whereas ACM from BDNF-treated astrocytes completely protected PC12 neurons from 3-NP-induced apoptosis. Both ACM from control and BDNF-treated astrocytes markedly reduced reactive oxygen species levels induced by 3-NP in PC12 cells. Our results demonstrate that BDNF protects astrocytes from cell death through TrkB-T1 signaling, exerts an antioxidant action, and induces release of neuroprotective factors from astrocytes. OPEN PRACTICES: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/.
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Apoptosis/efectos de los fármacos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Factor Neurotrófico Derivado del Encéfalo/farmacología , Glicoproteínas de Membrana/metabolismo , Fármacos Neuroprotectores/farmacología , Receptor trkB/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/genética , Azepinas/farmacología , Benzamidas/farmacología , Carbazoles/farmacología , Ciclo Celular/efectos de los fármacos , Células Cultivadas , Medio de Cultivo Libre de Suero/toxicidad , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Alcaloides Indólicos/farmacología , Glicoproteínas de Membrana/genética , Células PC12 , Proteínas Tirosina Quinasas/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Receptor trkB/genéticaRESUMEN
Astrocytes are now fully endorsed as key players in CNS functionality and plasticity. We recently showed that metabotropic glutamate receptor 3 (mGlu3R) activation by LY379268 promotes non-amyloidogenic cleavage of amyloid precursor protein (APP) in cultured astrocytes, leading to increased release of neuroprotective sAPPα. Furthermore, mGlu3R expression is reduced in hippocampal astrocytes from PDAPP-J20 mice, suggesting a role for these receptors in Alzheimer's disease. The present study enquires into the role of astroglial-derived neurotrophins induced by mGlu3R activation in neurotoxicity triggered by amyloid ß (Aß). Conditioned medium from LY379268-treated astrocytes protected hippocampal neurons from Aß-induced cell death. Immunodepletion of sAPPα from the conditioned medium prevented its protective effect. LY379268 induced brain-derived neurotrophic factor (BDNF) expression in astrocytes, and neutralizing BDNF from conditioned medium also prevented its neuroprotective effect on Aß neurotoxicity. LY379268 was also able to decrease Aß-induced neuron death by acting directly on neuronal mGlu3R. On the other hand, LY379268 increased Aß uptake in astrocytes and microglia. Indeed, and more importantly, a reduction in Aß-induced neuron death was observed when co-cultured with LY379268-pretreated astrocytes, suggesting a link between neuroprotection and increased glial phagocytic activity. Altogether, these results indicate a double function for glial mGlu3R activation against Aß neurotoxicity: (i) it increases the release of protective neurotrophins such as sAPPα and BDNF, and (ii) it induces amyloid removal from extracellular space by glia-mediated phagocytosis.
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Péptidos beta-Amiloides/metabolismo , Astrocitos/metabolismo , Microglía/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Aminoácidos/farmacología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Técnicas de Cocultivo , Medios de Cultivo Condicionados , Agonistas de Aminoácidos Excitadores/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Microglía/efectos de los fármacos , Microglía/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Neuroprotección/efectos de los fármacos , Neuroprotección/fisiología , Fármacos Neuroprotectores/farmacología , Fagocitosis/efectos de los fármacos , Fagocitosis/fisiología , Ratas Wistar , Receptores de Glutamato Metabotrópico/agonistasRESUMEN
Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.
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Inflamación/metabolismo , Microglía/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Neuropéptidos/metabolismo , Dolor/metabolismo , Adrenomedulina/metabolismo , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Ghrelina/metabolismo , Humanos , Mediadores de Inflamación , Leptina/metabolismo , Activación de Macrófagos , Neuralgia/metabolismo , Neuroglía/metabolismo , Neuropéptido Y/metabolismo , Proopiomelanocortina/metabolismo , Taquicininas/metabolismo , Péptido Intestinal Vasoactivo/metabolismoRESUMEN
α-melanocyte stimulating hormone (α-MSH) is an anti-inflammatory peptide, proved to be beneficial in many neuroinflammatory disorders acting through melanocortin receptor 4 (MC4R). We previously determined that rat microglial cells express MC4R and that NDP-MSH, an analog of α-MSH, induces PPAR-γ expression and IL-10 release in these cells. Given the great importance of modulation of glial activation in neuroinflammatory disorders, we tested the ability of NDP-MSH to shape microglial phenotype and to modulate Toll-like receptor (TLR)-mediated inflammatory responses. Primary rat cultured microglia were stimulated with NDP-MSH followed by the TLR2 agonist Pam3CSK4 or the TLR4 agonist LPS. NDP-MSH alone induced expression of the M2a/M2c marker Ag1 and reduced expression of the M2b marker Il-4rα and of the LPS receptor Tlr4. Nuclear translocation of NF-κB subunits p65 and c-Rel was induced by LPS and these effects were partially prevented by NDP-MSH. NDP-MSH reduced LPS- and Pam3CSK4-induced TNF-α release but did not affect TLR-induced IL-10 release. Also, NDP-MSH inhibited TLR2-induced HMGB1 translocation from nucleus to cytoplasm and TLR2-induced phagocytic activity. Our data show that NDP-MSH inhibits TLR2- and TLR4-mediated proinflammatory mechanisms and promotes microglial M2-like polarization, supporting melanocortins as useful tools for shaping microglial activation towards an alternative immunomodulatory phenotype.