Relationship between inflammation and oxidative stress and its effect on multiple sclerosis / Relación entre inflamación y estrés oxidativo y su efecto sobre la esclerosis múltiple

Introduction: This paper highlights the relationship of inflammation and oxidative stress as damage mechanisms of Multiple Sclerosis (MS), considered an inflammatory and autoimmune disease. Development: The oxidative stress concept has been defined by an imbalance between oxidants and antioxidants in favor of the oxidants. There is necessary to do physiological functions, like the respiration chain, but in certain conditions, the production of reactive species overpassed the antioxidant systems, which could cause tissue damage. On the other hand, it is well established that inflammation is a complex reaction in the vascularized connective tissue in response to diverse stimuli. However, an unregulated prolonged inflammatory process also can induce tissue damage. Conclusion: Both inflammation and oxidative stress are interrelated since one could promote the other, leading to a toxic feedback system, which contributes to the inflammatory and demyelination process in MS.(AU)

Introducción: Este trabajo destaca la relación de la inflamación y el estrés oxidativo como mecanismos de daño de la esclerosis múltiple, considerada enfermedad inflamatoria y autoinmune. Desarrollo: El concepto de estrés oxidativo se ha definido por un desequilibrio entre oxidantes y antioxidantes a favor de los oxidantes. Es necesario para realizar funciones fisiológicas, como la cadena respiratoria, pero en ciertas condiciones la producción de especies reactivas sobrepasaba los sistemas antioxidantes, lo que podría causar daño tisular. Por otro lado, está establecido que la inflamación es una reacción compleja en el tejido conectivo vascularizado en respuesta a diversos estímulos, pero un proceso inflamatorio prolongado no regulado también puede inducir daño tisular. Conclusión: Tanto la inflamación como el estrés oxidativo están interrelacionados entre sí, ya que uno de ellos podría promover al otro, dando lugar a un sistema de retroalimentación tóxico, que contribuye al desarrollo del proceso inflamatorio y desmielinizante en la esclerosis múltiple.(AU)

Relationship between inflammation and oxidative stress and its effect on multiple sclerosis.

INTRODUCTION: This paper highlights the relationship of inflammation and oxidative stress as damage mechanisms of Multiple Sclerosis (MS), considered an inflammatory and autoimmune disease. DEVELOPMENT: The oxidative stress concept has been defined by an imbalance between oxidants and antioxidants in favor of the oxidants. There is necessary to do physiological functions, like the respiration chain, but in certain conditions, the production of reactive species overpassed the antioxidant systems, which could cause tissue damage. On the other hand, it is well established that inflammation is a complex reaction in the vascularized connective tissue in response to diverse stimuli. However, an unregulated prolonged inflammatory process also can induce tissue damage. CONCLUSION: Both inflammation and oxidative stress are interrelated since one could promote the other, leading to a toxic feedback system, which contributes to the inflammatory and demyelination process in MS.

Estudio comparativo de melatonina contra los tratamientos inmunomoduladores (interferón beta y acetato de glatirámero) en un modelo murino de esclerosis múltiple / A comparative study of melatonin and immunomodulatory therapy with interferon beta and glatiramer acetate in a mouse model of multiple sclerosis

Introducción: La esclerosis múltiple (EM) es una enfermedad crónica desmielinizante autoinmune del sistema nervioso central (SNC) que produce neuroinflamación; un modelo es la encefalitis autoinmune experimental (EAE). La EM ha sido tratada con interferón beta (IFN-β) y acetato de glatirámero (AG). Se ha descrito que la melatonina (MLT) modula la respuesta del sistema inmune. El objetivo de este estudio fue observar el efecto de la administración de MLT contra los tratamientos de primera línea utilizados en la EM (IFN-β y AG).MétodosSe indujo EAE a ratas macho Sprague Dawley y se les administró IFN-β, AG o MLT. Se colectó líquido cefalorraquídeo (LCR) y se midieron citocinas proinflamatorias por multiplex, además del registro de la evaluación neurológica de la EAE.ResultadosTodos los animales inmunizados establecieron la EAE. Se evaluó el primer ciclo de recaída-remisión, observando que IFN-β y AG tienen mejores resultados que MLT en la evaluación clínica. La concentración en el LCR tanto de IL-1β como de IL-12p70 no se vio modificada por el modelo o por los tratamientos administrados. EL TNF-α se vio disminuido en el LCR por el IFN-β y la MLT bajo el modelo de EM.ConclusionesEs necesario realizar estudios posteriores para evaluar los mecanismos moleculares involucrados en el comportamiento de la MLT en la EAE, así como la cuantificación de otras citocinas en diferentes matrices biológicas para poder considerar la MLT como un agente antiinflamatorio regulador de la EM. (AU)

Introduction: Multiple sclerosis (MS) is a chronic, demyelinating, autoimmune disease of the central nervous system causing neuroinflammation. Experimental autoimmune encephalitis (EAE) is a model of the disease. MS is classically treated with interferon beta (IFN-β) and glatiramer acetate (GA). Melatonin (MLT) has been reported to modulate immune system responses. The aim of the present study is to analyse the effects of MLT administration in comparison with the first-line treatments for MS (IFN-β and GA).MethodsEAE was induced in male Sprague-Dawley rats; the animals subsequently received either IFN-β, GA, or MLT. Cerebrospinal fluid (CSF) samples were analysed by multiplex assay to determine the levels of proinflammatory cytokines. The neurological evaluation of EAE was also recorded.ResultsAll immunised animals developed EAE. We evaluated the first relapse-remission cycle, observing that IFN-β and GA had better results than MLT in the clinical evaluation. Neither EAE nor any of the treatments administered modified CSF IL-1β and IL-12p70 concentrations. However, IFN-β and MLT did decrease CSF TNF-α concentrations.ConclusionsFurther studies are needed to evaluate the molecular mechanisms involved in the behaviour of MLT in EAE, and to quantify other cytokines in different biological media in order for MLT to be considered an anti-inflammatory agent capable of regulating MS. (AU)

A comparative study of melatonin and immunomodulatory therapy with interferon beta and glatiramer acetate in a mouse model of multiple sclerosis. / Estudio comparativo de melatonina contra los tratamientos inmunomoduladores (interferón beta y acetato de glatirámero) en un modelo murino de esclerosis múltiple.

INTRODUCTION: Multiple sclerosis (MS) is a chronic, demyelinating, autoimmune disease of the central nervous system causing neuroinflammation. Experimental autoimmune encephalitis (EAE) is a model of the disease. MS is classically treated with interferon beta (IFN-ß) and glatiramer acetate (GA). Melatonin (MLT) has been reported to modulate immune system responses. The aim of the present study is to analyse the effects of MLT administration in comparison with the first-line treatments for MS (IFN-ß and GA). METHODS: EAE was induced in male Sprague-Dawley rats; the animals subsequently received either IFN-ß, GA, or MLT. Cerebrospinal fluid (CSF) samples were analysed by multiplex assay to determine the levels of proinflammatory cytokines. The neurological evaluation of EAE was also recorded. RESULTS: All immunised animals developed EAE. We evaluated the first relapse-remission cycle, observing that IFN-ß and GA had better results than MLT in the clinical evaluation. Neither EAE nor any of the treatments administered modified CSF IL-1ß and IL-12p70 concentrations. However, IFN-ß and MLT did decrease CSF TNF-α concentrations. CONCLUSIONS: Further studies are needed to evaluate the molecular mechanisms involved in the behaviour of MLT in EAE, and to quantify other cytokines in different biological media in order for MLT to be considered an anti-inflammatory agent capable of regulating MS.

[Cytokines and the nervous system: the relationship between seizures and epilepsy]. / Citocinas y sistema nervioso: relacion con crisis convulsivas y epilepsia.

INTRODUCTION. The immune system and the peripheral and central nervous system are in constant communication by means of messengers and signalling molecules released, such as cytokines, neuropeptides, neurohormones and neurotransmitters, among others. Seizures are defined as the transitory appearance of signs and symptoms that trigger an abnormally excessive neuronal activity in the brain. Following seizures the generation of a neuroinflammatory process has been observed to occur, with the consequent release of proinflammatory cytokines and inflammation-mediating molecules, which make the patient more prone to epilepsy. AIM. To offer evidence suggesting and supporting the role of cytokines in the appearance of seizures and in epilepsy, since these molecules have proven to have dual properties. DEVELOPMENT. The central nervous system, by means of the blood-brain barrier, restricts the flow of activated cells and inflammation mediators released from the peripheral system towards the brain parenchyma. Moreover, there is also another series of mechanisms that contributes to the 'selective and modified' immunity of the central nervous system. The purpose of all this series of events is to limit the responses of the immune system at central level, although it has been shown that in the central nervous system they are permanently under the control and regulation of the immune system. CONCLUSIONS. Cytokines in epilepsy play a dual role with pro- and anti-convulsive properties. Seizures do not induce the expression of cytokines only inside the brain, but also peripherally.

TITLE: Citocinas y sistema nervioso: relacion con crisis convulsivas y epilepsia.Introduccion. El sistema inmune y el sistema nervioso periferico y central se encuentran en constante comunicacion a traves de mensajeros y moleculas de señalizacion liberadas, como las citocinas, los neuropeptidos, las neurohormonas y los neurotransmisores, entre otros. Las convulsiones se definen como la aparicion transitoria de signos y sintomas que inducen una actividad neuronal excesiva anormal en el cerebro; despues de una crisis convulsiva, se ha observado la generacion de un proceso neuroinflamatorio, con la consecuente liberacion de citocinas proinflamatorias y de moleculas mediadoras de inflamacion, que predisponen a la epilepsia. Objetivo. Mostrar la evidencia que sugiere y apoya el papel de las citocinas en la aparicion de crisis convulsivas y en la epilepsia, ya que estas moleculas han demostrado propiedades duales. Desarrollo. El sistema nervioso central, a traves de la barrera hematoencefalica, restringe el flujo de celulas activadas y de mediadores de inflamacion liberados desde el sistema periferico hacia el parenquima cerebral; ademas, existe otra serie de mecanismos que contribuyen a la inmunidad 'selectiva y modificada' del sistema nervioso central. Toda esta serie de eventos tiene la finalidad de limitar respuestas del sistema inmune a nivel central, aunque se ha demostrado que en el sistema nervioso central se encuentran de manera permanente bajo el control y la regulacion del sistema inmune. Conclusiones. Las citocinas en la epilepsia muestran un papel dual con propiedades pro y anticonvulsionantes. Las convulsiones no solamente inducen la expresion de citocinas dentro del cerebro, sino tambien perifericamente.

Protective effects of tryptophan on neuro-inflammation in rats after administering lipopolysaccharide.

Tryptophan (TRP), which plays an important role in immune system regulation, protein synthesis, serotonin (5-HT) and melatonin production, is a potent endogenous free radical scavenger and antioxidant. The aim of this work was to determine the efficacy of TRP in neuro-inflammation induced by systemic administration of lipopolysacharide (LPS, 20mg/kg) which promotes the synthesis of free radical (LPO: MDA and 4-HDA), and pro-inflammatory cytokine Interferon-γ (IFN-γ) in different brain regions (cerebral cortex and hippocampus) of rats. Experiments were performed on adult female, pregnant and lactating rats fed with a diet of TRP content (0.5mg/100g protein), cerebral cortex and hippocampus were evaluated for lipid peroxidation (LPO) products, nitrites, nitrates and plasmatic concentration of IFN-γ. LPO levels in LPS+TRP groups were significantly decreased than that obtained in the LPS group. However, there were no observed differences in plasmatic levels of nitrites and nitrates as well as IFN-γ, neither in the cerebral cortex or hippocampus. The TRP has protective effect in the oxidative damage in a model of endotoxic shock in the breading nurslings induced by the systemic administration of LPS, acting as a scavenger of free radicals. So, it can be proposed as an innocuous protector agent in the endotoxic shock process.

Role of p38 MAPK and pro-inflammatory cytokines expression in glutamate-induced neuronal death of neonatal rats.

Pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6 rises significantly during neuronal damage and activate the signaling p38 MAPK pathway, which is involved in the apoptotic (AP) neuronal death. Systemic administration of glutamate as monosodium salt (MSG) to newborn animals induces neuronal death, however whether neurons die by AP or necrosis through MAPK p38 pathway activation it is unknown. In this study, TNF-alpha, IL-1beta and IL-6 expression levels, AP neuronal death and cellular type that produces TNF-alpha was also identified in the cerebral cortex (CC) and striatum (St) of rats at 8, 10, and 14 days of age after neonatal exposure to MSG. TNF-alpha production and AP neuronal death was significantly increased in the CC at PD8-10, and in the St in all ages studied by excitotoxicity effect induced with MSG. This effect was completely inhibited by SB203580 (p38 inhibitor) in both regions studied. TNF-alpha, IL-1beta and IL-6 RNAm increased after MSG administration, whereas SB203580 did not modify their expression. These data indicates that neuronal death induced by excitotoxicity appears to be mediated through p38 signaling pathway activated by TNF-alpha and their inhibition may have an important neuroprotective role as part of anti-inflammatory therapeutic strategy.

Protective effects of melatonin against caustic esophageal burn injury in rats.

Caustic ingestion is one of the most life-threatening events in the pediatric age group, which requires the immediate management and subsequent treatment of its most significant complication, i.e. alterations in esophageal structure. We investigated whether melatonin could reduce the esophageal burn damage induced by sodium hydroxide. It was assumed that melatonin could be effective because of its function as a direct free radical scavenger, its antioxidative actions and its ability to diminish tissue hydroxyproline (HP) levels. Esophageal burns were induced in male rats by the administration of 10% sodium hydroxide. Lipid peroxidation (LPO) products were then measured at the following times: 0, 1, 6, 24, 48 and 72 hr after treatment. Tissue HP concentrations in the injured area were assessed at 14 days after the administration of sodium hydroxide. The groups received either systemic melatonin or normal saline. There were two, non-ischemic, sham control groups treated with or without melatonin. LPO products, malondialdehyde (MDA) and 4-hydroxyalkenal (4-HDA), increased immediately after the administration of sodium hydroxide; this indicates the participation of free radicals in the development of damage. Melatonin diminished the oxidative response and the amount of HP in the late phase of the lesion. Melatonin reduced oxidative damage in the early phase of the esophageal burns induced by sodium hydroxide.

The orbital Harderian gland of the male atlantic bottlenose dolphin (Tursiops truncatus): a morphological study.

The ultrastructure of the Atlantic Bottlenose dolphin Harderian gland (HG) has been described but some questions remain unanswered. The purpose of this work was to define the gland's structure, ultrastructure and the differences between cells (types I and II) of the male dolphin using optic, fluorescence and electron transmission microscopy. Three different cells were observed under optic and fluorescence microscopic examination, while only two cell types (types I and II) were distinguished by electron transmission microscopy. Type I (oval nuclear envelope) exhibited three different cell populations and type II (indented nuclear envelope) exhibited two different cell populations. Although, we observed both types of vesicles in both types of cells they differed, principally, in quantity. The glands also possessed prominent duct systems, with three orders of complexity. The dolphin orbital HG appears to function as a mixed heterologous gland with two types of cells that exhibit both types of vesicles and other distinguishable differences.

Monosodium glutamate-induced damage in liver and kidney: a morphological and biochemical approach.

It has been demonstrated that high concentrations of monosodium glutamate in the central nervous system induce neuronal necrosis and damage in retina and circumventricular organs. In this model, the monosodium glutamate is used to induce an epileptic state; one that requires highly concentrated doses. The purpose of this study was to evaluate the toxic effects of the monosodium glutamate in liver and kidney after an intra-peritoneal injection. For the experiment, we used 192 Wistar rats to carry out the following assessments: a) the quantification of the enzymes alanine aminotransferase and aspartate aminotransferase, b) the quantification of the lipid peroxidation products and c) the morphological evaluation of the liver and kidney. During the experiment, all of these assessments were carried out at 0, 15, 30 and 45 min after the intra-peritoneal injection. In the rats that received monosodium glutamate, we observed increments in the concentration of alanine aminotransferase and aspartate aminotransferase at 30 and 45 min. Also, an increment of the lipid peroxidation products, in kidney, was exhibited at 15, 30 and 45 min while in liver it was observed at 30 and 45 min. Degenerative changes were observed (edema-degeneration-necrosis) at 15, 30 and 45 min.

Different patterns in the histology and autofluorescence of the Harderian glands of the Syrian Hamster, rat, mouse, Mongolian gerbil and guinea pig.

The purpose of this study was to compare the natural fluorescence in the Harderian glands of the Syrian hamster, rat, mouse, Mongolian gerbil and guinea pig (both sexes). For each species, 10 animals (five males and five females) were used. Histological autofluorescence studies were performed using a fluorescence microscope (450-490 nm filter). Two different types of fluorescent cells were observed in both hamster (type AFI high intensity and type AFII, low fluorescence) and rat (type AFI, low fluorescence and type AFII, high fluorescence) Harderian glands. The fluorescence was basally located in all mice cells, whereas it was observed near the epithelial cell nuclei in the Mongolian gerbil (occupying two-thirds and one-third of the cells in males and females, respectively). A high intensity of fluorescence was present throughout the acinar cells in the guinea pig. The patterns of fluorescence identified exhibited a sexual dimorphism in all species studied. These results demonstrate that the Harderian glands of the animal species examined exhibit a variety of histological autofluorescence patterns.

Genotoxicity of paraquat: micronuclei induced in bone marrow and peripheral blood are inhibited by melatonin.

The ability of melatonin to influence paraquat-induced genotoxicity was tested using micronucleated polychromatic erythrocytes as an index of damage in both bone marrow and peripheral blood cells of mice. Melatonin (10 mg/kg) or an equal volume of saline were administered intraperitoneally (ip) to mice 30 min prior to an ip injection of paraquat (20 mg/kgx2), and thereafter at 6-h intervals until the conclusion of the study (72 h). The number of the micronucleated polychromatic erythrocytes increased after paraquat administration both in peripheral blood and bone marrow cells. Melatonin administration to paraquat-treated mice significantly reduced micronuclei formation in both peripheral blood and bone marrow cells; these differences were apparent at 24, 48 and 72 h after paraquat administration. The induction of micronuclei was time-dependent with peak values occurring at 24 and 48 h. The reduction in paraquat-related genotoxicity by melatonin is likely due in part to the antioxidant activity of the indole. We did not observe effects of melatonin over paraquat in paraquat+melatonin groups incubated at 0, 60 and 120 min. Mitomycin C, which was used as a positive control, also caused the expected large rises in micronuclei in both bone marrow and peripheral blood cells at 24, 48 and 72 h after its administration.

Effects of melatonin on the Harderian gland of lipopolysaccharide-treated rats: morphological observations.

Melatonin is a free radical scavenger and antioxidant. This indol is reported to efficiently scavenge both hydroxyl and peroxyl radicals and it also reduces both in vitro and in vivo tissue damage due to oxidants which generate oxygen toxic radicals. Lipopolysaccharide (LPS) administration induces oxidative damage in various tissues mainly due to its ability to increase reactive oxygen species. In the present work, we studied the morphological changes and lipid peroxidation in the Harderian gland after LPS administration and the effects of melatonin in preventing the induced changes. Hyperchromasia, vesicular degeneration, necrosis and infiltration with macrophages, monocytes and neutrophils were observed in the LPS-treated group (10 mg/kg, intraperitonally [i.p.]). Also, a typical structure of the glandular acini of the gland exhibited diffuse damage. In the LPS rats treated with melatonin (10 mg/kg, i.p.), a diminished number of infiltrative cells was seen, and cloudy swelling was reduced, as was nuclear hyperchromasia. Neither necrosis nor vesicular degeneration were noted in the melatonin-treated rats, and in general, glandular structure was preserved. Lipid peroxidation products increased significantly within six hours after LPS administration, and melatonin treatment decreased the LPS-dependent lipid peroxidation products. These data together suggest that melatonin protects the Harderian gland against LPS toxicity in terms of morphological damage.

Neurotoxicity of dextrorphan.

BACKGROUND: The noncompetitive NMDA antagonists phencyclidine (PCP) and dizocilpine (MK-801) have been considered for use as neuroprotective therapeutic agents, although both produce injury in neurons of cingulate and retrosplenial cortices in rodents. The low-affinity, noncompetitive NMDA antagonist dextrorphan has been considered for use as a neuroprotective therapeutic drug. The aim of the present work was to evaluate the neurotoxicity of dextrorphan. METHODS: Sprague-Dawley male rats were used and injected with either saline or dextrorphan (30 mg/kg i.p.). The animals were sacrificed 30 min later, and the brain was examined for histopathological changes. RESULTS: After systemic administration of the drug, hyperchromatic and shrunken nuclei with chromatin condensation and disruption were observed. Also, granular and vacuolated cytoplasm was apparent in pyramidal neurons in the retrosplenial (posterior cingulate) cortex. Status spongiosus (spongy degeneration) of the neuropil was also detected. CONCLUSIONS: Morphological changes are similar to those described previously, which are induced by high-affinity, noncompetitive NMDA antagonists, such as MK-801.