RESUMEN
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.
Asunto(s)
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
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.
Asunto(s)
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
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
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.
Asunto(s)
Astrocitos/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Expresión Génica , Receptor de Melanocortina Tipo 4/metabolismo , Adenilil Ciclasas/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Células Cultivadas , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Interferón gamma/farmacología , Interferón gamma/fisiología , Lipopolisacáridos/farmacología , FN-kappa B/metabolismo , Péptidos Cíclicos/farmacología , Ratas , Ratas Wistar , Receptor de Melanocortina Tipo 4/agonistas , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Transducción de Señal , alfa-MSH/análogos & derivados , alfa-MSH/farmacología , alfa-MSH/fisiologíaRESUMEN
In a previous work we showed that the melanocortin alpha-melanocyte-stimulating hormone (α-MSH) exerts anti-inflammatory action through melanocortin 4 receptor (MC4R) in vivo in rat hypothalamus. In this work, we examined the effect of α-MSH on the expression of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) and their receptors in primary cultured rat hypothalamic neurons. We also investigated α-MSH's possible mechanism/s of action. α-MSH (5 µM) decreased TNF-α expression induced by 24h administration of a combination of bacterial lipopolysaccharide (LPS, 1 µg/ml) plus interferon-γ (IFN-γ, 50 ng/ml). Expression of TNF-α and IL-1ß receptors TNFR1, TNFR2 and IL-1RI, was up-regulated by LPS+IFN-γ whereas α-MSH did not modify basal or LPS+IFN-γ-induced-TNFRs or IL-1RI expression. Both α-MSH and LPS+IFN-γ treatments increased CREB activation. α-MSH did not modify NF-κB activation induced by LPS+IFN-γ in hypothalamic neurons. In conclusion, our data show that α-MSH reduces TNF-α expression in hypothalamic neurons by a mechanism which could be mediated by CREB. The regulation of inflammatory processes in the hypothalamus by α-MSH might help to prevent neurodegeneration resulting from inflammation.
Asunto(s)
Hipotálamo/inmunología , Hipotálamo/metabolismo , Interferón gamma/antagonistas & inhibidores , Lipopolisacáridos/fisiología , Receptores Tipo I de Factores de Necrosis Tumoral , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , alfa-MSH/fisiología , Animales , Células Cultivadas , Femenino , Regulación de la Expresión Génica/inmunología , Hipotálamo/citología , Interferón gamma/biosíntesis , Interferón gamma/genética , Lipopolisacáridos/antagonistas & inhibidores , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neuronas/inmunología , Neuronas/metabolismo , Neuronas/patología , Ratas , Ratas Wistar , Receptores Tipo I de Factores de Necrosis Tumoral/biosíntesis , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Inflammatory processes contribute widely to the development of neurodegenerative diseases. The expression of many inflammatory mediators was found to be increased in central nervous system (CNS) disorders suggesting that these molecules are major contributors to neuronal damage. Melanocortins are neuropeptides that have been implicated in a wide range of physiological processes. The melanocortin alpha-melanocyte stimulating hormone (alpha-MSH) has pleiotropic functions and exerts potent anti-inflammatory actions by antagonizing the effects of pro-inflammatory cytokines and by decreasing important inflammatory mediators. Five subtypes of melanocortin receptors (MC1R-MC5R) have been identified. Of these, the MC4 receptor is expressed predominantly throughout the CNS. Evidence of effectiveness of selective MC4R agonists in modulating inflammatory processes and their low toxicity suggest that these molecules may be useful in the treatment of CNS disorders with an inflammatory component. This review describes the involvement of the MC4R in central anti-inflammatory effects of melanocortins and discusses the potential value of MC4R agonists for the treatment of inflammatory-related disorders.
Asunto(s)
Encefalitis/metabolismo , Receptor de Melanocortina Tipo 4/metabolismo , alfa-MSH/metabolismo , Animales , Encéfalo/metabolismo , Humanos , Receptores de Melanocortina/metabolismoRESUMEN
alpha-MSH is involved in reproductive processes and can regulate the expression of lordosis, an important component of female reproductive behavior in rats and many other species. In this study, we investigated the effects of MSH peptides on lordosis behavior when injected in medial preoptic area (POA) of ovariectomised rats primed with estradiol. The results show an increase in lordotic activity after bilateral administration of alpha-MSH and gamma-MSH. Interestingly, the treatment with the MC4 receptor antagonist HS014 did not block the stimulatory effect of alpha-MSH. Moreover, the injection of HS014 did not itself modify the lordosis quotient. Nitric oxide has been suggested to play a crucial role in the regulation of lordosis behavior via stimulation of guanylyl cyclase to synthesize cGMP. In order to determine the participation of NO in the effect of the melanocortins, another group of rats were treated with L-NAME, an inhibitor of NOS, alone or 15 min before the injection of alpha-MSH or gamma-MSH. The injection of L-NAME into the POA of E-primed rats 15 min before the test for sexual receptivity did not modify significantly the lordosis quotient at the two doses examined. The treatment with L-NAME at the lowest dose completely abolished the stimulatory effect of alpha-MSH and gamma-MSH on sexual behavior. The results indicate that the effects of MSH peptides on female sexual behavior in this area are mediated through specific MC receptor, that could be the MC3 receptor and that NO mediates the melanocortins effects.
Asunto(s)
Hormonas Estimuladoras de los Melanocitos/fisiología , Óxido Nítrico/fisiología , Área Preóptica/fisiología , Receptor de Melanocortina Tipo 3/fisiología , Conducta Sexual Animal/fisiología , Animales , Mapeo Encefálico , Femenino , Ratas , Ratas Wistar , alfa-MSH/fisiología , gamma-MSH/fisiologíaRESUMEN
Ghrelin is a peptide hormone produced and secreted from the stomach. Hypothalamic injection of the peptide increases food intake but it is not known if the peptide affects other brain regions. We measured several behavioral parameters such as anxiety (elevated plus maze), memory retention (step down test), and food intake after injections of different doses of the peptide in the hippocampus, amygdala, and dorsal raphe nucleus (DRN). The injection of ghrelin in the hippocampus and DRN significantly and dose dependently increased food intake in relation to controls rats, while injections into the amygdala did not affect the food intake. We also show for the first time that ghrelin clearly and dose dependently increases memory retention in the hippocampus, amygdala, and DRN. Moreover, ghrelin at different potencies induced anxiogenesis in these brain structures while the highest dose of 3 nmol/microl was effective in all of them. The comparison of sensitivity of each brain structure indicates a specific role of them for each of the behaviors studied. The results provide new insight in to the anatomical substrate and the functional role of extrahypothalamic ghrelin targets in the CNS.
Asunto(s)
Amígdala del Cerebelo/fisiología , Hipocampo/fisiología , Hormonas Peptídicas/fisiología , Núcleos del Rafe/fisiología , Animales , Conducta Animal , Relación Dosis-Respuesta a Droga , Conducta Alimentaria , Ghrelina , Masculino , Aprendizaje por Laberinto , Memoria , Hormonas Peptídicas/metabolismo , Péptidos/química , Ratas , Ratas Wistar , Especificidad por Sustrato , Factores de TiempoRESUMEN
Ghrelin is a peptide found in the hypothalamus and stomach that stimulates food intake and whose circulating concentrations are affected by nutritional state. Very little is known about other central behavioral effects of ghrelin, and thus, we investigated the effects of ghrelin on anxiety and memory retention. The peptide was injected intracerebroventricularly in rats and we performed open-field, plus-maze, and step-down tests (inhibitory avoidance). The administration of ghrelin increased freezing in the open field and decreased the number of entries into the open spaces and the time spent on the open arms in the plus-maze, indicating an anxiogenic effect. Moreover, the peptide increased in a dose-dependent manner the latency time in the step-down test. A rapid and prolonged increase in food intake was also observed. Our results indicate that ghrelin induces anxiogenesis in rats. Moreover, we show for the first time that ghrelin increases memory retention, suggesting that the peptide may influence processes in the hippocampus.