RESUMEN
Postnatal hippocampal neurogenesis is essential for learning and memory. Hippocampal neural precursor cells (NPCs) can be induced to proliferate and differentiate into either glial cells or dentate granule cells. Notably, hippocampal neurogenesis decreases dramatically with age, partly due to a reduction in the NPC pool and a decrease in their proliferative activity. Alpha-melanocyte-stimulating hormone (α-MSH) improves learning, memory, neuronal survival and plasticity. Here, we used postnatally-isolated hippocampal NPCs from Wistar rat pups (male and female combined) to determine the role of the melanocortin analog [Nle4, D-Phe7]-α-MSH (NDP-MSH) in proliferation and fate acquisition of NPCs. Incubation of growth-factor deprived NPCs with 10 nM NDP-MSH for 6 days increased the proportion of Ki-67- and 5-bromo-2'-deoxyuridine (BrdU)-positive cells, compared to the control group, and these effects were blocked by the MC4R antagonist JKC-363. NDP-MSH also increased the proportion of glial fibrillar acidic protein (GFAP)/Ki-67, GFAP/sex-determining region Y-box2 (SOX2) and neuroepithelial stem cell protein (NESTIN)/Ki-67-double positive cells (type-1 and type-2 precursors). Finally, NDP-MSH induced peroxisome proliferator-activated receptor (PPAR)-γ protein expression, and co-incubation with the PPAR-γ inhibitor GW9662 prevented the effect of NDP-MSH on NPC proliferation and differentiation. Our results indicate that in vitro activation of MC4R in growth-factor-deprived postnatal hippocampal NPCs induces proliferation and promotes the relative expansion of the type-1 and type-2 NPC pool through a PPAR-γ-dependent mechanism. These results shed new light on the mechanisms underlying the beneficial effects of melanocortins in hippocampal plasticity and provide evidence linking the MC4R and PPAR-γ pathways in modulation of hippocampal NPC proliferation and differentiation.
Asunto(s)
Diferenciación Celular , Proliferación Celular , Hipocampo , Células-Madre Neurales , Neurogénesis , Ratas Wistar , Receptor de Melanocortina Tipo 4 , alfa-MSH , Animales , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/citología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Células-Madre Neurales/fisiología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Receptor de Melanocortina Tipo 4/metabolismo , alfa-MSH/farmacología , alfa-MSH/análogos & derivados , Femenino , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Masculino , Neurogénesis/efectos de los fármacos , Neurogénesis/fisiología , Ratas , Células Cultivadas , Factores de Transcripción SOXB1/metabolismo , Animales Recién Nacidos , Proteína Ácida Fibrilar de la Glía/metabolismo , PPAR gamma/metabolismoRESUMEN
Astrocytes are glial cells that perform several fundamental physiological functions within the brain. They can control neuronal activity and levels of ions and neurotransmitters, and release several factors that modulate the brain environment. Over the past few decades, our knowledge of astrocytes and their functions has rapidly evolved. Neurodegenerative diseases are characterized by selective degeneration of neurons, increased glial activation, and glial dysfunction. Given the significant role played by astrocytes, there is growing interest in their potential therapeutic role. However, defining their contribution to neurodegeneration is more complex than was previously thought. This review summarizes the main functions of astrocytes and their involvement in neurodegenerative diseases, highlighting their neurotoxic and neuroprotective ability.
RESUMEN
In light of the rising evidence of the association between viral and bacterial infections and neurodegeneration, we aimed at revisiting the infectious hypothesis of Alzheimer's disease and analyzing the possible implications of COVID-19 neurological sequelae in long-term neurodegeneration. We wondered how SARS-CoV-2 could be related to the amyloid-ß cascade and how it could lead to the pathological hallmarks of the disease. We also predict a paradigm change in clinical medicine, which now has a great opportunity to conduct prospective surveillance of cognitive sequelae and progression to dementia in people who suffered severe infections together with other risk factors for Alzheimer's disease.
RESUMEN
Subtype 3 metabotropic glutamate receptor (mGlu3R) displays a broad range of neuroprotective effects. We previously demonstrated that mGlu3R activation in astrocytes protects hippocampal neurons from Aß neurotoxicity through stimulation of both neurotrophin release and Aß uptake. Alternative-spliced variants of mGlu3R were found in human brains. The most prevalent variant, mGlu3Δ4, lacks exon 4 encoding the transmembrane domain and can inhibit ligand binding to mGlu3R. To date, neither its role in neurodegenerative disorders nor its endogenous expression in CNS cells has been addressed. The present paper describes for the first time an association between altered hippocampal expression of mGlu3Δ4 and Alzheimer's disease (AD) in the preclinical murine model PDAPP-J20, as well as a deleterious effect of mGlu3Δ4 in astrocytes. As assessed by western blot, hippocampal mGlu3R levels progressively decreased with age in PDAPP-J20 mice. On the contrary, mGlu3Δ4 levels were drastically increased with aging in nontransgenic mice, but prematurely over-expressed in 5-month-old PDAPP-J20-derived hippocampi, prior to massive senile plaque deposition. Also, we found that mGlu3Δ4 co-precipitated with mGlu3R mainly in 5-month-old PDAPP-J20 mice. We further showed by western blot that primary cultured astrocytes and neurons expressed mGlu3Δ4, whose levels were reduced by Aß, thereby discouraging a causal effect of Aß on mGlu3Δ4 induction. However, heterologous expression of mGlu3Δ4 in astrocytes induced cell death, inhibited mGlu3R expression, and prevented mGlu3R-dependent Aß glial uptake. Indeed, mGlu3Δ4 promoted neurodegeneration in neuron-glia co-cultures. These results provide evidence of an inhibitory role of mGlu3Δ4 in mGlu3R-mediated glial neuroprotective pathways, which may lie behind AD onset.
Asunto(s)
Enfermedad de Alzheimer , Receptores de Glutamato Metabotrópico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Astrocitos/metabolismo , Células Cultivadas , Ratones , Ratones Transgénicos , Isoformas de Proteínas/metabolismo , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismoRESUMEN
Huntington's disease (HD) is a neurodegenerative genetic disorder caused by a CAG repeat expansion in the huntingtin gene. HD causes motor, cognitive, and behavioral dysfunction. Since no existing treatment affects the course of this disease, new treatments are needed. Inflammation is frequently observed in HD patients before symptom onset. Neuroinflammation, characterized by the presence of reactive microglia, astrocytes and inflammatory factors within the brain, is also detected early. However, in comparison to other neurodegenerative diseases, the role of neuroinflammation in HD is much less known. Work has been dedicated to altered microglial and astrocytic functions in the context of HD, but less attention has been given to glial participation in neuroinflammation. This review describes evidence of inflammation in HD patients and animal models. It also discusses recent knowledge on neuroinflammation in HD, highlighting astrocyte and microglia involvement in the disease and considering anti-inflammatory therapeutic approaches.
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Enfermedad de Huntington , Animales , Astrocitos , Modelos Animales de Enfermedad , Humanos , Inflamación/genética , Microglía , Enfermedades NeuroinflamatoriasRESUMEN
BACKGROUND: Evidence shows significant heterogeneity in astrocyte gene expression and function. We previously demonstrated that brain-derived neurotrophic factor (BDNF) exerts protective effects on whole brain primary cultured rat astrocytes treated with 3-nitropropionic acid (3NP), a mitochondrial toxin widely used as an in vitro model of Huntington's disease (HD). Therefore, we now investigated 3NP and BDNF effects on astrocytes from two areas involved in HD: the striatum and the entire cortex, and their involvement in neuron survival. METHODS: We prepared primary cultured rat cortical or striatal astrocytes and treated them with BDNF and/or 3NP for 24 h. In these cells, we assessed expression of astrocyte markers, BDNF receptor, and glutamate transporters, and cytokine release. We prepared astrocyte-conditioned medium (ACM) from cortical and striatal astrocytes and tested its effect on a cellular model of HD. RESULTS: BDNF protected astrocytes from 3NP-induced death, increased expression of its own receptor, and activation of ERK in both cortical and striatal astrocytes. However, BDNF modulated glutamate transporter expression differently by increasing GLT1 and GLAST expression in cortical astrocytes but only GLT1 expression in striatal astrocytes. Striatal astrocytes released higher amounts of tumor necrosis factor-α than cortical astrocytes in response to 3NP but BDNF decreased this effect in both populations. 3NP decreased transforming growth factor-ß release only in cortical astrocytes, whereas BDNF treatment increased its release only in striatal astrocytes. Finally, we evaluated ACM effect on a cellular model of HD: the rat striatal neuron cell line ST14A expressing mutant human huntingtin (Q120) or in ST14A cells expressing normal human huntingtin (Q15). Neither striatal nor cortical ACM modified the viability of Q15 cells. Only ACM from striatal astrocytes treated with BDNF and ACM from 3NP + BDNF-treated striatal astrocytes protected Q120 cells, whereas ACM from cortical astrocytes did not. CONCLUSIONS: Data suggest that cortical and striatal astrocytes respond differently to mitochondrial toxin 3NP and BDNF. Moreover, striatal astrocytes secrete soluble neuroprotective factors in response to BDNF that selectively protect neurons expressing mutant huntingtin implicating that BDNF modulation of striatal astrocyte function has therapeutic potential against neurodegeneration.
Asunto(s)
Astrocitos/metabolismo , Factor Neurotrófico Derivado del Encéfalo/toxicidad , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Proteína Huntingtina/biosíntesis , Nitrocompuestos/toxicidad , Propionatos/toxicidad , Animales , Animales Recién Nacidos , Astrocitos/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Femenino , Expresión Génica , Humanos , Proteína Huntingtina/genética , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mutación/efectos de los fármacos , Mutación/fisiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuroprotección/efectos de los fármacos , Neuroprotección/fisiología , Ratas , Ratas WistarRESUMEN
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.
Asunto(s)
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.
Asunto(s)
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.
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Microglía/efectos de los fármacos , Receptor Toll-Like 2/agonistas , Receptor Toll-Like 4/agonistas , alfa-MSH/análogos & derivados , Animales , Células Cultivadas , Interleucina-10/metabolismo , Lipopéptidos/farmacología , Lipopolisacáridos/farmacología , Microglía/metabolismo , Ratas , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , alfa-MSH/farmacologíaRESUMEN
The immune system is an important modulator of learning, memory and neural plasticity. Interleukin 1ß (IL-1ß), a pro-inflammatory cytokine, significantly affects several cognitive processes. Previous studies by our group have demonstrated that intrahippocampal administration of IL-1ß impairs reconsolidation of contextual fear memory. This effect was reversed by the melanocortin alpha-melanocyte-stimulating hormone (α-MSH). The mechanisms underlying the effect of IL-1ß on memory reconsolidation have not yet been established. Therefore, we examined the effect of IL-1ß on glutamate release, ERK phosphorylation and the activation of the transcription factor zinc finger- 268 (zif268) during reconsolidation. Our results demonstrated that IL-1ß induced a significant decrease of glutamate release after reactivation of the fear memory and this effect was related to calcium concentration in hippocampal synaptosomes. IL-1ß also reduced ERK phosphorylation and zif268 expression in the hippocampus. Central administration of α-MSH prevented the decrease in glutamate release, ERK phosphorylation and zif268 expression induced by IL-1ß. Our results establish possible mechanisms involved in the detrimental effect of IL-1ß on memory reconsolidation and also indicate that α-MSH may exert a beneficial modulatory role in preventing IL-1ß effects.
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Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Ácido Glutámico/metabolismo , Hipocampo/metabolismo , Interleucina-1beta/farmacología , Trastornos de la Memoria/metabolismo , Memoria/efectos de los fármacos , alfa-MSH/farmacología , Animales , Calcio/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Miedo/fisiología , Hipocampo/efectos de los fármacos , Masculino , Fosforilación , Ratas , Ratas Wistar , Sinaptosomas/metabolismoRESUMEN
Amyloid precursor protein (APP) shedding yields the Alzheimer's disease (AD)-related peptide amyloid ß (Aß) through ß- and γ-secretase cleavage. Alternatively, α-secretase cleavage generates a soluble and neuroprotective fragment (sAPPα) while precludes the production of Aß. Although metabotropic glutamate (mGlu) receptors were associated with induction of sAPPα production in astrocytes, there was no further evidence regarding the specific subtype receptor or the mechanisms involved in this action. In the present study, we used the dual mGlu2/3 receptor agonist LY379268, which in pure astrocyte cultures selectively activates mGlu3 receptor subtype since mGlu2 receptor subtype is not expressed by these cells. We showed that LY379268 incremented sAPPα release from cultured astrocytes by inducing α-secretases expression, whereas it decreased ß-secretase levels. LY379268-induced increase of PPAR-γ levels could be involved in the effect of the agonist on sAPPα release. Using the PDAPP-J20 murine model of AD we described a strong reduction in mGlu2/3 receptor expression in the hippocampus of 5- and 14-month-old transgenic mice compared to control littermates. Moreover, mGlu3 receptor expression is also decreased specifically in hippocampal astrocytes of these transgenic animals as a function of age. Therefore, diminished levels of hippocampal mGlu3 receptors might have implications in the development of the disease in these transgenic mice considering the anti-amyloidogenic action of mGlu3 receptors in astrocytes.
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Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Astrocitos/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Envejecimiento , Aminoácidos/farmacología , Precursor de Proteína beta-Amiloide/genética , Animales , Astrocitos/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Células Cultivadas , Agonistas de Aminoácidos Excitadores/metabolismo , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación , Ratas , Ratas Wistar , Receptores de Glutamato Metabotrópico/agonistasRESUMEN
Astrocytes exert a wide variety of functions with paramount importance in brain physiology. After injury or infection, astrocytes become reactive and they respond by producing a variety of inflammatory mediators that help maintain brain homeostasis. Loss of astrocyte functions as well as their excessive activation can contribute to disease processes; thus, it is important to modulate reactive astrocyte response. Melanocortins are peptides with well-recognized anti-inflammatory and neuroprotective activity. Although melanocortin efficacy was shown in systemic models of inflammatory disease, mechanisms involved in their effects have not yet been fully elucidated. Central anti-inflammatory effects of melanocortins and their mechanisms are even less well known, and, in particular, the effects of melanocortins in glial cells are poorly understood. Of the five known melanocortin receptors (MCRs), only subtype 4 is present in astrocytes. MC4R has been shown to mediate melanocortin effects on energy homeostasis, reproduction, inflammation, and neuroprotection and, recently, to modulate astrocyte functions. In this review, we will describe MC4R involvement in anti-inflammatory, anorexigenic, and anti-apoptotic effects of melanocortins in the brain. We will highlight MC4R action in astrocytes and discuss their possible mechanisms of action. Melanocortin effects on astrocytes provide a new means of treating inflammation, obesity, and neurodegeneration, making them attractive targets for therapeutic interventions in the CNS.
Asunto(s)
Astrocitos/metabolismo , Receptor de Melanocortina Tipo 4/metabolismo , Animales , Metabolismo Energético , Humanos , Inflamación/metabolismo , Melanocortinas/metabolismoRESUMEN
Brain inflammation plays a central role in numerous brain pathologies. Microglia and astrocytes are the main effector cells that become activated when an inflammatory process takes place within the central nervous system. α-melanocyte-stimulating hormone (α-MSH) is a neuropeptide with proven anti-inflammatory properties. It binds with highest affinity to the melanocortin receptor 4 (MC4R), which is present in astrocytes and upon activation triggers anti-inflammatory pathways. The aim of this research was to identify anti-inflammatory mediators that may participate in the immunomodulatory effects of melanocortins in glial cells. Since peroxisome proliferator-activated receptors (PPARs) have recently been implicated in the modulation of inflammation, we investigated the effect of an α-MSH analog, [Nle(4), D-Phe(7)]-α-MSH (NDP-α-MSH), on PPAR-ß and PPAR-γ gene and protein expression in rat primary astrocytes and microglia. We initially demonstrated that rat primary microglia express MC4R and showed that treatment with NDP-α-MSH increases PPAR-γ protein levels and strongly decreases PPAR-ß levels in both astrocytes and microglia. We also showed that extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated signaling is partially involved in these effects in a cell-specific fashion. Finally, we showed that NDP-α-MSH stimulates the release of the anti-inflammatory cytokines IL-10 and TGF-ß from microglia and astrocytes, respectively. The presented data suggest a role for IL-10 and TGF-ß in the protective action of melanocortins and a connection between MC4R pathway and that of the nuclear receptor PPAR-γ. This is the first report providing evidence that MC4R is expressed in rat primary microglia and that melanocortins modulate PPAR levels in glial cells. Our findings provide new insights into the mechanisms underlying the activation of glial MC4R and open perspectives for new therapeutic strategies for the treatment of inflammation-mediated brain diseases.
Asunto(s)
Astrocitos/efectos de los fármacos , Citocinas/metabolismo , Microglía/efectos de los fármacos , PPAR gamma/metabolismo , PPAR-beta/metabolismo , alfa-MSH/farmacología , Animales , Astrocitos/metabolismo , Western Blotting , Inmunohistoquímica , Microglía/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , alfa-MSH/químicaRESUMEN
Astrocytes are currently studied intensively because of their now highlighted relevance as key players with neurons that modulate a wide range of central functions, from synaptic plasticity and synaptogenesis to regulation of metabolic and neuroinflammatory processes. Since the discovery of mGlu3 receptors on astrocytes, accumulating evidence supports a role of these receptors not only in maintaining synaptic homeostasis and treating psychiatric disorders but also in promoting astrocyte survival in several pathologic conditions. This review focuses on providing up-to-date knowledge regarding effects of activating astroglial mGlu3 receptors on psychiatric disorders, astrocyte and neuronal survival, and neurodegenerative diseases. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
Asunto(s)
Astrocitos/fisiología , Terapia Molecular Dirigida/métodos , Fármacos Neuroprotectores/uso terapéutico , Receptores de Glutamato Metabotrópico/fisiología , Animales , Agonistas de Aminoácidos Excitadores/farmacología , Agonistas de Aminoácidos Excitadores/uso terapéutico , Humanos , Ligandos , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/fisiopatología , Modelos Neurológicos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/fisiopatología , Fármacos Neuroprotectores/farmacología , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/biosíntesisRESUMEN
Melanocortin 4 receptors (MC4R) are mainly expressed in the brain. We previously showed that the anti-inflammatory action of α-melanocyte-stimulating hormone (α-MSH) in rat hypothalamus and in cultured astrocytes involved MC4R activation. However, MC4R mechanisms of action remain undetermined. Since brain-derived neurotrophic factor (BDNF) may be mediating MC4R hypothalamic anorexigenic actions, we determined melanocortin effects on BDNF expression in rat cultured astrocytes and certain mechanisms involved in MC4R signaling. α-MSH and its analogue NDP-MSH, induced production of cAMP in astrocytes. This effect was completely blocked by the MC4R antagonist, HS024. We found that NDP-MSH increased BDNF mRNA and protein levels in astrocytes. The effect of NDP-MSH on BDNF expression was abolished by the adenylate cyclase inhibitor SQ22536, and decreased by the PKA inhibitor Rp-cAMP. Since melanocortins are immunomodulators, we investigated their actions with bacterial lipopolysaccharide (LPS) and interferon-γ (IFN-γ) stimulus. Although both α-MSH and LPS+IFN-γ increased cAMP responding element binding protein (CREB) activation, LPS+IFN-γ did not modify BDNF expression. On the other hand, α-MSH did not modify basal or LPS+IFN-γ-induced nuclear factor-κB activation. Our results show for the first time that MC4R activation in astrocytes induces BDNF expression through cAMP-PKA-CREB pathway without involving NF-κB.