RESUMEN
Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease characterized by multifocal perivascular infiltration of immune cells in the central nervous system (CNS). Cordycepin (3'-deoxyadenosine), an adenosine analogue initially extracted from the fungus Cordyceps militarisa, is one of the candidates that has multiple actions. We investigated that cordycepin attenuated the activation of LPS-induced mouse bone marrow-derived dendritic cells (BMDCs) and human monocyte-derived dendritic cells (MoDCs) through the inhibition of the AKT, ERK, NFκB, and ROS pathways and impaired the migration of BMDCs through the downregulation of adhesion molecules and chemokine receptors in vitro. In experimental autoimmune encephalomyelitis (EAE) model, preventive treatment with cordycepin decreased the expression of trafficking factors in the CNS, inhibited the secretion of inflammatory cytokines (IFN-γ, IL-6, TNF-α, and IL-17), and attenuated disease symptoms. A chemokine array indicated that cordycepin treatment reversed the high levels of CCL6, PARRES2, IL-16, CXCL10, and CCL12 in the brain and spinal cord of EAE mice, consistent with the RNA-seq data. Moreover, cordycepin suppressed the release of neuroinflammatory cytokines by activated microglial cells, macrophages, Th17 cells, Tc1 cells, and Th1 cells in vitro. Furthermore, cordycepin treatment exerted therapeutic effects on attenuating the disease severity in the early disease onset stage and late disease progression stage. Our study suggests that cordycepin treatment may not only prevent the occurrence of MS by inhibiting DC activation and migration but also potentially ameliorates the progression of MS by reducing neuroinflammation, which may provide insights into the development of new approaches for the treatment of MS.
Asunto(s)
Desoxiadenosinas/uso terapéutico , Encefalomielitis Autoinmune Experimental/prevención & control , Mediadores de Inflamación/antagonistas & inhibidores , Leucocitos/efectos de los fármacos , Animales , Línea Celular Transformada , Células Cultivadas , Desoxiadenosinas/farmacología , Relación Dosis-Respuesta a Droga , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Humanos , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Leucocitos/inmunología , Leucocitos/metabolismo , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/inducido químicamente , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/prevención & control , Células RAW 264.7 , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/metabolismo , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
The aim of this study is to investigate the potential preventive and therapeutic effects of nobiletin by evaluating the expression of cytokines associated with inflammatory reactions in an autoimmune encephalomyelitis mouse model. A total of 60 male C57BL/6 mice aged between 8 and 10 weeks were used. Mice were divided into six groups (n = 10 mice per group): control, EAE, low-prophylaxis, high-prophylaxis, low-treatment and high-treatment. Experimental autoimmune encephalomyelitis (EAE) was induced by myelin oligodendrocyte glycoprotein (MOG) and pertussis toxin. Nobiletin was administered in low (25 mg/kg) and high (50 mg/kg) doses, intraperitoneally. The prophylactic and therapeutic effects of nobiletin on brain tissue and spinal cord were evaluated by expression of interleukin-1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), interferon gamma (IFNγ), IL-6, IL-10 and transforming growth factor-beta (TGF-ß) using immunohistochemistry and real-time polymerase chain reaction (RT-PCR). Prophylactic and therapeutic use of nobiletin inhibited EAE-induced increase of TNF-α, IL-1ß and IL-6 activities to alleviate inflammatory response in brain and spinal cord. Moreover, nobiletin supplement dramatically increased the IL-10, TGF-ß and IFNγ expressions in prophylaxis and treatment groups compared with the EAE group in the brain and spinal cord. The results obtained from this study show that prophylactic and therapeutic nobiletin modulates expressions of proinflammatory and antiinflammatory cytokines in brain and spinal cord dose-dependent manner in EAE model. These data demonstrates that nobiletin has a potential to attenuate inflammation in EAE mouse model. These experimental findings need to be supported by clinical studies.
Asunto(s)
Antioxidantes/uso terapéutico , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Flavonas/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Animales , Antioxidantes/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/patología , Citocinas/efectos de los fármacos , ADN Complementario/biosíntesis , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/prevención & control , Flavonas/farmacología , Inmunohistoquímica , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Esclerosis Múltiple/prevención & control , ARN/genética , ARN/aislamiento & purificación , Reacción en Cadena en Tiempo Real de la Polimerasa , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Médula Espinal/patologíaRESUMEN
OBJECTIVES: Therapeutic approaches for multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), are accompanied by various undesirable side effects. Owing to the anti-inflammatory and antioxidant effects of walnut, we investigated its effects on the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. METHODS: After EAE induction in mice, the treated group was gavaged daily with walnut oil. The weights and clinical symptoms were monitored daily for 21 days following the onset of symptoms. The spleens and brains of the mouse were removed and used for ELISA and histological studies. RESULTS: The average disease severity and plaque formation in the brains of the walnut oil-treated group were significantly lower (P < 0.05) than those of the untreated group. Stimulated splenocytes of the treated group expressed significantly less INF-γ and interleukin (IL)-17 than the untreated group with no significant differences in IL-10 or IL-5 production. In serum from the treated group, IL-17 expression was also significantly less than in the untreated group, while IL-10 was greater (P < 0.05). CONCLUSION: Walnut oil significantly reduced disease severity, inhibited plaque formation, and altered cytokine production. More studies are required to identify the mechanism of action of walnut oil as a valuable supplement in the treatment of MS.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/patología , Juglans , Esclerosis Múltiple/metabolismo , Aceites de Plantas/administración & dosificación , Animales , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/prevención & control , Femenino , Ratones Endogámicos C57BL , Esclerosis Múltiple/prevención & control , Bazo/efectos de los fármacos , Bazo/metabolismoRESUMEN
The autoimmune neurological disease, Multiple Sclerosis (MS), have increased at alarming rates in the Western society over the last few decades. While there are numerous efforts to develop novel treatment approaches, there is an unmet need to identify preventive strategies. We explored whether central nervous system (CNS) autoimmunity can be prevented through dietary manipulation using a spontaneous autoimmune encephalomyelitis mouse model. We report that the nutritional supplementation of non-fermentable fiber, common components of a vegetarian diet, in early adult life, prevents autoimmune disease. Dietary non-fermentable fiber alters the composition of the gut microbiota and metabolic profile with an increase in the abundance of long-chain fatty acids. Immune assays revealed that cecal extracts and a long chain fatty acid but not cecal lysates promoted autoimmune suppressive TH2 immune responses, demonstrating that non-fermentable fiber-induced metabolic changes account for the beneficial effects. Overall, these findings identify a non-invasive dietary strategy to prevent CNS autoimmunity and warrants a focus on nutritional approaches in human MS.
Asunto(s)
Fibras de la Dieta/farmacología , Encefalomielitis Autoinmune Experimental/prevención & control , Animales , Enfermedades Autoinmunes/prevención & control , Sistema Nervioso Central/inmunología , Fibras de la Dieta/uso terapéutico , Modelos Animales de Enfermedad , Ácidos Grasos/inmunología , Microbioma Gastrointestinal , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/microbiología , Ratones , Células Th2/inmunologíaRESUMEN
Tolerogenic dendritic cells (DCs) have the ability to induce regulatory T cells and play an important role in preventing chronic inflammatory and autoimmune diseases. We have identified a novel compound, 14-dehydroergosterol, from Koji, a Japanese traditional food material fermented with fungi. 14-dehydroergosterol is an ergosterol analogue with a conjugated double bond, but the activity of 14-dehydroergosterol is much higher than that of ergosterol. 14-dehydroergosterol induces the conversion of murine bone marrow (BM)-derived DCs and differentiated DCs into tolerogenic DCs, in which the production of IL-12 is suppressed and that of IL-10 is increased. In a co-culture experiment, DCs treated with 14-dehydroergosterol induced the conversion of naïve CD4-positive T cells into regulatory T cells. In a murine model of multiple sclerosis, experimental autoimmune encephalopathy, 14-dehydroergosterol suppressed the clinical score and inflammatory responses of myeloid DCs and T cells to myelin oligodendrocyte glycoprotein. 14-dehydroergosterol-treated human DCs induced from PBMCs also showed a tolerogenic phenotype. This is the first report to identify a novel compound, 14-dehydroergosterol, that induces DCs to convert to a tolerogenic type. 14-dehydroergosterol is contained in various fermented foods based on Koji, so 14-dehydroergosterol might be a helpful aid to prevent chronic inflammatory and autoimmune diseases.
Asunto(s)
Antiinflamatorios/farmacología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Ergosterol/análogos & derivados , Animales , Antiinflamatorios/química , Aspergillus/metabolismo , Células de la Médula Ósea/citología , Células Dendríticas/citología , Células Dendríticas/metabolismo , Evaluación Preclínica de Medicamentos , Encefalomielitis Autoinmune Experimental/prevención & control , Ergosterol/química , Ergosterol/farmacología , Femenino , Fermentación , Interleucina-10/metabolismo , Ratones , Fenotipo , Triticum/química , Triticum/metabolismo , Triticum/microbiologíaRESUMEN
BACKGROUND: In multiple sclerosis, coagulation factors have been shown to modulate inflammation. In this translational study, we investigated whether long-term anticoagulation with warfarin or rivaroxaban has beneficial effects on the course of autoimmune experimental encephalomyelitis (EAE). METHODS: Female SJL/J mice treated with anticoagulants namely warfarin or rivaroxaban were immunized with PLP139-151. Stable anticoagulation was maintained throughout the entire experiment. Mice without anticoagulation treated with the vehicle only were used as controls. The neurological deficit was recorded during the course of EAE, and histopathological analyses of inflammatory lesions were performed. RESULTS: In preventive settings, both treatment with warfarin and rivaroxaban reduced the maximum EAE score as compared to the control group and led to a reduction of inflammatory lesions in the spinal cord. In contrast, therapeutic treatment with warfarin had no beneficial effects on the clinical course of EAE. Signs of intraparenchymal hemorrhage at the site of the inflammatory lesions were not observed. CONCLUSION: We developed long-term anticoagulation models that allowed exploring the course of EAE under warfarin and rivaroxaban treatment. We found a mild preventive effect of both warfarin and rivaroxaban on neurological deficits and local inflammation, indicating a modulation of the disease induction by anticoagulation.
Asunto(s)
Anticoagulantes/uso terapéutico , Encefalomielitis Autoinmune Experimental/prevención & control , Rivaroxabán/uso terapéutico , Warfarina/uso terapéutico , Animales , Encéfalo/anatomía & histología , Modelos Animales de Enfermedad , Impedancia Eléctrica , Encefalomielitis Autoinmune Experimental/sangre , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/inmunología , Células Endoteliales/efectos de los fármacos , Adyuvante de Freund/toxicidad , Ratones , Proteína Proteolipídica de la Mielina/toxicidad , Fragmentos de Péptidos/toxicidad , Distribución Aleatoria , Rivaroxabán/sangre , Porcinos , Trombina/metabolismo , Factores de TiempoRESUMEN
Acetate supplementation increases brain acetyl-CoA metabolism, alters histone and non-histone protein acetylation, increases brain energy reserves, and is anti-inflammatory and neuroprotective in rat models of neuroinflammation and neuroborreliosis. To determine the impact acetate supplementation has on a mouse model of multiple sclerosis, we quantified the effect treatment had on injury progression, spinal cord lipid content, phospholipase levels, and myelin structure in mice subjected to experimental autoimmune encephalomyelitis (EAE). EAE was induced by inoculating mice with a myelin oligodendrocyte glycoprotein peptide fragment (MOG35-55 ), and acetate supplementation was maintained with 4 g/kg glyceryl triacetate by a daily oral gavage. Acetate supplementation prevented the onset of clinical signs in mice subject to EAE compared to control-treated mice. Furthermore, acetate supplementation prevented the loss of spinal cord ethanolamine and choline glycerophospholipid and phosphatidylserine in mice subjected to EAE compared to EAE animals treated with water. Treatment increased saturated and monounsaturated fatty acid levels in phosphatidylserine compared to controls suggesting that acetate was utilized to increase spinal cord fatty acid content. Also, acetate supplementation prevented the loss of spinal cord cholesterol in EAE animals but did not change cholesteryl esters. Treatment significantly increased GD3 and GD1a ganglioside levels in EAE mice when compared to EAE mice treated with water. Treatment returned levels of phosphorylated and non-phosphorylated cytosolic phospholipase A2 (cPLA2 ) levels back to baseline and based on FluoroMyelin™ histochemistry maintained myelin structural characteristics. Overall, these data suggest that acetate supplementation may modulate lipid metabolism in mice subjected to EAE.
Asunto(s)
Acetilcoenzima A/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Ácidos Grasos/metabolismo , Metabolismo de los Lípidos/fisiología , Médula Espinal/enzimología , Acetatos/uso terapéutico , Animales , Conducta Animal/efectos de los fármacos , Cromatografía en Capa Delgada , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/prevención & control , Femenino , Metabolismo de los Lípidos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Vaina de Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/toxicidad , Fragmentos de Péptidos/toxicidad , Fosfolipasas A2/metabolismo , Médula Espinal/efectos de los fármacos , Estadísticas no Paramétricas , Triglicéridos/farmacologíaRESUMEN
Multiple sclerosis (MS), a neuroinflammatory disease, has few treatment options, none entirely adequate. We studied whether prolonged electrical microstimulation of a hindbrain region (the nucleus raphe magnus) can attenuate experimental autoimmune encephalomyelitis, a murine model of MS induced by MOG35-55 injection. Eight days after symptoms emerged, a wireless electrical stimulator with an attached microelectrode was implanted cranially, and daily intermittent stimulation was begun in awake, unrestrained mice. The thoracic spinal cord was analyzed for changes in histology (on day 29) and gene expression (on day 37), with a focus on myelination and cytokine production. Controls, with inactive implants, showed a phase of disease exacerbation on days 19-25 that stimulation for >16days eliminated. Prolonged stimulation also reduced numbers of infiltrating immune cells and increased numbers of myelinated axons. It additionally lowered genetic expression of some pro-inflammatory cytokines (interferon gamma and tumor necrosis factor) and platelet-derived growth factor receptor alpha, a marker of oligodendrocyte precursors, while raising expression of myelin basic protein. Studies of restorative treatments for MS might profitably consider ways to stimulate the raphe magnus, directly or via its inputs, or to emulate its serotonergic and peptidergic output.
Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Núcleos del Rafe/fisiopatología , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Estimulación Eléctrica , Terapia por Estimulación Eléctrica , Encefalomielitis Autoinmune Experimental/prevención & control , Femenino , Expresión Génica , Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/prevención & control , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , Médula Espinal/metabolismo , Médula Espinal/patologíaRESUMEN
OBJECTIVE: To explore the therapeutic effect and possible mechanism of Huangqi glycoprotein (HQGP) on the development of experimental autoimmune encephalomyelitis (EAE). METHODS: Female C57BL/6 mice were immunized subcutaneously with myelin oligodendrocyte glycoprotein peptide-35-55 (MOG35-55) and divided into HQGP-treated group and EAE control group. Clinical score and body mass were recorded every other day. Inflammatory cell infiltrations of spinal cord were observed by HE and immunofluorescence staining. The cell viability of splenic mononuclear cells (MNCs) was detected by MTT assay. The release of NO was measured by Griess method. The levels of TNF-α, IL-6 and IFN-γ were determined by ELISA. The subtypes of CD4(+)T cells were analyzed by flow cytometry. RESULTS: HQGP treatment delayed the onset of EAE, attenuated the clinical symptoms and inhibited CD68(+) macrophage infiltration into the central nervous system. HQGP inhibited the viability of splenic MNCs, downregulated the secretion of NO, TNF-α, IL-6, and increased the secretion of IFN-γ. In addition, HQGP treatment effectively increased the numbers of CD4(+)CD25(+) T cells, CD4(+)IL-10(+) T cells and CD4(+)IFN-γ(+) T cells. CONCLUSION: HQGP relieve the inflammation of EAE via reducing the number of T cell subsets and inhibiting the secretion of inflammatory cytokines.
Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Encefalomielitis Autoinmune Experimental/prevención & control , Glicoproteínas/farmacología , Factores Inmunológicos/farmacología , Animales , Antígenos CD/inmunología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/inmunología , Antígenos de Diferenciación Mielomonocítica/metabolismo , Astragalus propinquus/química , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito/inmunología , Óxido Nítrico/inmunología , Óxido Nítrico/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Médula Espinal/metabolismo , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/metabolismo , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
Multiple sclerosis is a chronic, inflammatory and demyelinating disease of the central nervous system (CNS). As there is no cure for this disease, new therapeutic strategies and prophylactic measures are necessary. We recently described the therapeutic activity of the association between myelin oligodendrocyte glycoprotein peptide (MOG) and active vitamin D3 (VitD) against experimental autoimmune encephalomyelitis (EAE). The objective of this work was to evaluate the prophylactic potential of this association in EAE. C57BL/6 mice were vaccinated with MOG in the presence of VitD and then subjected to EAE induction. Animals were euthanized 7 and 19days after disease induction and the following parameters were evaluated: body weight, clinical score, inflammatory process in the CNS, amount of dendritic cells (DCs) and regulatory T cells in the spleen and cytokine production by spleen and CNS cell cultures. Vaccination with MOG associated with VitD determined a drastic reduction in clinical score, body weight loss, CNS inflammation, DCs maturation and also in the production of cytokines by CNS and spleen cell cultures. Collectively, our data indicate that this association prevents EAE development. A similar effect from specific self-antigens associated with VitD is expected in other autoimmune conditions and deserves to be experimentally appraised.
Asunto(s)
Sistema Nervioso Central/patología , Encefalomielitis Autoinmune Experimental/prevención & control , Glicoproteína Mielina-Oligodendrócito/toxicidad , Vitamina D/administración & dosificación , Vitaminas/administración & dosificación , Animales , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta Inmunológica , Esquema de Medicación , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/patología , Femenino , Citometría de Flujo , Adyuvante de Freund/toxicidad , Ratones , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito/inmunología , Neuronas/metabolismo , Bazo/patología , Factores de TiempoRESUMEN
Inflammation, demyelination, oligodendrocyte (OLG) death, and axonal degeneration are primary characteristics of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). OLGs generate myelin sheaths that surround axons, while damage to OLGs leads to demyelination and neurological functional deficit. Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to effectively ameliorate clinical signs in EAE. Its therapeutic mechanism has, however, not been completely elucidated. In the present study, we found that MAT retarded the disease process, attenuated the clinical severity of EAE rats, ameliorated inflammation and demyelination, and suppressed the apoptosis of OLGs in the central nervous system (CNS) of EAE rats. In addition, MAT markedly blocked increased expression of the proNGF-p75(NTR) death signaling complex, which is known to mediate OLG death in EAE animals. At the same time, MAT also prevented a decrease in the levels of NGF and its receptor TrkA, which together mediate the cell survival pathway and differentiation of OLGs. ProNGF, NGF, and the downstream effector proteins play an important role in the growth, differentiation, and apoptosis of OLGs as well as the reparative response to neuronal damage. These findings thus indicate that MAT improves clinical severity of EAE in part by reducing OLG apoptosis via restoring the ratios of proNGF:NGF and the respective receptors p75(NTR):TrkA in vivo. Taken together, these results suggest that MAT may be a promising agent for MS treatment based on its protective effect on OLGs.
Asunto(s)
Alcaloides/farmacología , Encefalomielitis Autoinmune Experimental/prevención & control , Factores de Crecimiento Nervioso/metabolismo , Precursores de Proteínas/metabolismo , Quinolizinas/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Axones/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/prevención & control , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Técnica del Anticuerpo Fluorescente , Inmunohistoquímica , Fármacos Neuroprotectores/farmacología , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Oligodendroglía/patología , Fitoterapia/métodos , Ratas Wistar , Sophora/química , MatrinasRESUMEN
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and is associated with demyelination, neurodegeneration, and sensitivity to oxidative stress. In this work, we administered a nanodroplet formulation of pomegranate seed oil (PSO), denominated Nano-PSO, to mice induced for experimental autoimmune encephalomyelitis (EAE), an established model of MS. PSO comprises high levels of punicic acid, a unique polyunsaturated fatty acid considered as one of the strongest natural antioxidants. We show here that while EAE-induced mice treated with natural PSO presented some reduction in disease burden, this beneficial effect increased significantly when EAE mice were treated with Nano-PSO of specific size nanodroplets at much lower concentrations of the oil. Pathological examinations revealed that Nano-PSO administration dramatically reduced demyelination and oxidation of lipids in the brains of the affected animals, which are hallmarks of this severe neurological disease. We propose that novel formulations of natural antioxidants such as Nano-PSO may be considered for the treatment of patients suffering from demyelinating diseases. On the mechanistic side, our results demonstrate that lipid oxidation may be a seminal feature in both demyelination and neurodegeneration.
Asunto(s)
Antioxidantes/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Nanopartículas/química , Animales , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Enfermedades Desmielinizantes/tratamiento farmacológico , Enfermedades Desmielinizantes/patología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/prevención & control , Femenino , Humanos , Lípidos/química , Malondialdehído/metabolismo , Ratones Endogámicos C57BL , Modelos Biológicos , Esclerosis Múltiple/patología , Oxidación-Reducción , Tamaño de la Partícula , Aceites de Plantas/administración & dosificación , Aceites de Plantas/farmacología , Aceites de Plantas/uso terapéutico , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
Experimental autoimmune encephalomyelitis (EAE) is a CD4⺠T cell mediated inflammatory demyelinating disease that is induced in mice by administration of peptides derived from myelin proteins. We developed EAE in SJL mice by administration of PLP139-151 peptide. The effect of treating these mice with 1α,25-Dihydroxyvitamin D3 (vitamin D3), or with monomethyl fumarate (MMF) was then examined. We observed that both vitamin D3 and MMF inhibited and/or prevented EAE in these mice. These findings were corroborated with isolating natural killer (NK) cells from vitamin D3-treated or MMF-treated EAE mice that lysed immature or mature dendritic cells. The results support and extend other findings indicating that an important mechanism of action for drugs used to treat multiple sclerosis (MS) is to enhance NK cell lysis of dendritic cells.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Colecalciferol/farmacología , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/prevención & control , Fumaratos/farmacología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Maleatos/farmacología , Animales , Células Dendríticas/ultraestructura , Encefalomielitis Autoinmune Experimental/inmunología , Citometría de Flujo , Ratones , Proteína Proteolipídica de la Mielina , FenotipoRESUMEN
OBJECTIVE: To evaluate the effect of Tanreqing injection on axon myelin in the mouse brain of experimental autoimmune encephalomyelitis (EAE). METHODS: An EAE model was established by myelin oligodendrocyte glycoprotein (MOG)35-55 immunization in C57BL/6 mice. Mice were randomly divided into the following groups: normal, model, prednisone acetate (PA) (6 mg/kg), Tanreqing high dose (5.14 mL/kg), Tanreqing low dose (2.57 mL/kg). On the day of immunization, both Tanreqing groups were treated by intraperitoneal injection, with the PA group treated by intragastrical perfusion after T cell response, and the other groups treated with saline. Changes in body weight, neurological deficit score, incidence rate, mortality rate, and course of disease were observed for all mice. Brain tissue was isolated and stained with hematoxylin-eosin, and pathological investigations performed to evaluate axon myelin damage by transmission electron microscopy (TEM). Myelin basic protein and microtubule associated protein-2 were analyzed by immunohistochemistry. RESULTS: Tanreqing injection significantly prolonged EAE latency and decreased the neurological deficit score, alleviated infiltration of inflammatory cells in the focus area, up-regulated hippocampal MBP expression at the acute stage and the remission stage, and increased microtubule associated protein-2 expression in the EAE brain to varying degrees in the acute stage. TEM analysis indicated that Tanreqing injection alleviates myelin damage in the EAE mouse and maintains the integrity of circular layer structures and alleviates axon mitochondrial swelling. CONCLUSION: Tanreqing injection alleviates EAE symptoms.
Asunto(s)
Axones/efectos de los fármacos , Medicamentos Herbarios Chinos/administración & dosificación , Encefalomielitis Autoinmune Experimental/prevención & control , Vaina de Mielina/efectos de los fármacos , Animales , Axones/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Proteína Básica de Mielina/genética , Proteína Básica de Mielina/metabolismo , Vaina de Mielina/genética , Vaina de Mielina/metabolismoRESUMEN
BACKGROUND: Glatiramer acetate (GA, Copaxone, Copolymer-1) is an FDA approved drug for the treatment of MS and it is very effective in suppressing neuroinflammation in experimental autoimmune encephalitis (EAE), an animal model of MS. Although this drug was designed to inhibit pathogenic T cells, the exact mechanism of EAE/MS suppression by GA is still not well understood. Previously we presented evidence that platelets become activated and promote neuroinflammation in EAE, suggesting a possible pathogenic role of platelets in MS and EAE. We hypothesized that GA could inhibit neuroinflammation by affecting not only immune cells but also platelets. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the effect of GA on the activation of human platelets in vitro: calcium influx, platelet aggregation and expression of activation markers. Our results in human platelets were confirmed by in-vitro and in-vivo studies of modulation of functions of platelets in mouse model. We found that GA inhibited thrombin-induced calcium influx in human and mouse platelets. GA also decreased thrombin-induced CD31, CD62P, CD63, and active form of αIIbß3 integrin surface expression and formation of platelet aggregates for both mouse and human platelets, and prolonged the bleeding time in mice by 2.7-fold. In addition, we found that GA decreased the extent of macrophage activation induced by co-culture of macrophages with platelets. CONCLUSIONS: GA inhibited the activation of platelets, which suggests a new mechanism of GA action in suppression of EAE/MS by targeting platelets and possibly preventing their interaction with immune cells such as macrophages. Furthermore, the reduction in platelet activation by GA may have additional cardiovascular benefits to prevent thrombosis.
Asunto(s)
Calcio/metabolismo , Péptidos/farmacología , Activación Plaquetaria/efectos de los fármacos , Trombina/farmacología , Adyuvantes Inmunológicos/farmacología , Animales , Antígeno B7-2/metabolismo , Tiempo de Sangría , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Células Cultivadas , Técnicas de Cocultivo , Encefalomielitis Autoinmune Experimental/sangre , Encefalomielitis Autoinmune Experimental/prevención & control , Acetato de Glatiramer , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Transporte Iónico/efectos de los fármacos , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Ratones Endogámicos C57BL , Esclerosis Múltiple/sangre , Esclerosis Múltiple/prevención & control , Selectina-P/metabolismo , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismoRESUMEN
Pertussis toxin (PTx) has various effects in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). This study was designed to explore the protective effects of PTx of different doses and subunits. EAE model was induced with myelin oligodendrocyte glycoprotein (MOG35-55, 200 ug) plus complete Freund's adjuvant in 6-7 week-old female C57BL/6 mice. PTx reduced clinical deficits of EAE by 91.3%. This reduction in clinical deficits was achieved by attenuating demyelination by 75.5%. Furthermore, PTx reduced the lymphocyte infiltration, deactivated microglia activation and changed T cell profile by increasing T helper (type 1 and 2) and T regulatory cells.
Asunto(s)
Encefalomielitis Autoinmune Experimental/prevención & control , Microglía/efectos de los fármacos , Toxina del Pertussis/uso terapéutico , Linfocitos T/efectos de los fármacos , Análisis de Varianza , Animales , Presentación de Antígeno/efectos de los fármacos , Proteínas de Unión al Calcio/metabolismo , Proliferación Celular/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Encefalomielitis Autoinmune Experimental/inducido químicamente , Citometría de Flujo , Factores de Transcripción Forkhead/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/metabolismo , Glicoproteína Mielina-Oligodendrócito/toxicidad , Examen Neurológico , Fragmentos de Péptidos/toxicidad , Toxina del Pertussis/farmacología , Bazo/patología , Factores de TiempoRESUMEN
The role of vitamin D supplementation in preventing multiple sclerosis (MS) and/or treating MS progression is an area of significant research interest. We detail the current status of the ongoing research in this field, and note the lack of class 1 evidence from well-conducted, large, double-blind, placebo-controlled studies of vitamin D supplementation in the prevention and/or treatment of MS. We have been able to provide some guidelines for practitioners based on the substantial burden of supportive evidence for the use of vitamin D in MS as summarised here. These guidelines may provide some support to those clinicians who treat people with MS and their families.
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Vitamina D/uso terapéutico , Animales , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/prevención & control , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/prevención & control , Guías de Práctica Clínica como Asunto/normasRESUMEN
The present study was designed to determine whether epimedium flavonoids (EF) had effect on the development of experimental autoimmune encephalomyelitis (EAE) in rats and to elucidate its underlying mechanisms. EAE was induced by immunization of adult female Lewis rats with partially purified myelin basic protein (MBP) prepared from guinea-pig spinal cord homogenate. EF was administrated intragastrically once a day after immunization until day 14 post immunization (p.i.). Histopathological staining, enzyme-linked immunosorbent assay (ELISA), biochemical methods and western blotting approaches were used to evaluate the disease incidence and severity, neuroinflammatory and neurotrophic response in the central nervous system (CNS). Intragastrical administration of EF (20 and 60 mg/kg) significantly reduced clinical score of neurological deficit in EAE rats; alleviated demyelination and inflammatory infiltration; and inhibited astrocytes activation, production of proinflammatory molecules such as interleukin-1ß (IL-1ß), tumour necrosis factor-α (TNF-α), nitric oxide (NO) and nuclear transcription factor (NF-κB) in the spinal cord of EAE rats. Treatment with EF also enhanced the expression of 2', 3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) and nerve growth factor (NGF), increased the number of oligodendrocytes and protected the ultrastructure of myelin sheaths and axons in the spinal cord of EAE rats. Our results showed that EF inhibited the development of partial MBP-induced EAE in rats. This effect involved reducing neuroinflammation and enhancing myelination and neurotrophins and our findings suggest that EF may be useful for the treatment of multiple sclerosis.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Sistema Nervioso Central/efectos de los fármacos , Medicamentos Herbarios Chinos/uso terapéutico , Encefalomielitis Autoinmune Experimental/prevención & control , Epimedium/química , Flavonoides/uso terapéutico , Neuroinmunomodulación/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Astrocitos/efectos de los fármacos , Astrocitos/inmunología , Astrocitos/metabolismo , Astrocitos/patología , Axones/efectos de los fármacos , Axones/inmunología , Axones/metabolismo , Axones/ultraestructura , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Enfermedades Desmielinizantes/etiología , Enfermedades Desmielinizantes/prevención & control , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/fisiopatología , Femenino , Flavonoides/administración & dosificación , Flavonoides/análisis , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/inmunología , Vaina de Mielina/metabolismo , Vaina de Mielina/ultraestructura , Factores de Crecimiento Nervioso/metabolismo , Oligodendroglía/efectos de los fármacos , Oligodendroglía/inmunología , Oligodendroglía/metabolismo , Oligodendroglía/patología , Distribución Aleatoria , Ratas , Ratas Endogámicas Lew , Índice de Severidad de la Enfermedad , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Médula Espinal/metabolismo , Médula Espinal/patología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
The green tea component epigallocatechin-3-gallate (EGCG) may be beneficial in autoimmune diseases; however, the underlying mechanisms are not well understood. In this study, we determined the effect of EGCG on the development of experimental autoimmune encephalomyelitis, an animal model for human multiple sclerosis, and the underlying mechanisms. Female C57BL/6 mice were fed EGCG (0%, 0.15%, 0.3%, and 0.6% in diet) for 30 days and then immunized with specific antigen myelin oligodendrocyte glycoprotein 35-55. EGCG dose dependently attenuated clinical symptoms and pathological features (leukocyte infiltration and demyelination) in the central nervous system and inhibited antigen-specific T-cell proliferation and delayed-type hypersensitivity skin response. We further showed that EGCG reduced production of interferon-γ, IL-17, IL-6, IL-1ß, and tumor necrosis factor-α; decreased types 1 and 17 helper T cells (Th1 and Th17, respectively); and increased regulatory T-cell populations in lymph nodes, the spleen, and the central nervous system. Moreover, EGCG inhibited expression of transcription factors T-box expressed in T cells and retinoid-related orphan receptor-γt, the specific transcription factor for Th1 and Th17 differentiation, respectively; the plasma levels of intercellular adhesion molecule 1; and CCR6 expression in CD4(+) T cells. These results indicate that EGCG may attenuate experimental autoimmune encephalomyelitis autoimmune response by inhibiting immune cell infiltration and modulating the balance among pro- and anti-autoimmune CD4(+) T-cell subsets. Thus, we identified a novel mechanism that underlies EGCG's beneficial effect in autoimmune disease.
Asunto(s)
Linfocitos T CD4-Positivos/efectos de los fármacos , Catequina/análogos & derivados , Encefalomielitis Autoinmune Experimental/prevención & control , Fármacos Neuroprotectores/farmacología , Subgrupos de Linfocitos T/efectos de los fármacos , Animales , Linfocitos T CD4-Positivos/inmunología , Catequina/farmacología , Proliferación Celular , Citocinas/metabolismo , Enfermedades Desmielinizantes/prevención & control , Suplementos Dietéticos , Regulación hacia Abajo , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Ratones , Ratones Endogámicos C57BL , Monocitos/metabolismo , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/prevención & control , Proteínas de la Mielina/antagonistas & inhibidores , Glicoproteína Mielina-Oligodendrócito , Neuritis/prevención & control , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Distribución Aleatoria , Proteínas de Dominio T Box/antagonistas & inhibidores , Subgrupos de Linfocitos T/inmunologíaRESUMEN
We have evaluated the effects of the carbon monoxide-releasing molecule CORM-A1 [Na(2) (BH(3) CO(2) ); ALF421] on the development of relapsing-remitting experimental allergic encephalomyelitis (EAE) in SJL mice, an established model of multiple sclerosis (MS). The data show that the prolonged prophylactic administration of CORM-A1 improves the clinical and histopathological signs of EAE, as shown by a reduced cumulative score, shorter duration and a lower cumulative incidence of the disease as well as milder inflammatory infiltrations of the spinal cords. This study suggests that the use of CORM-A1 might represent a novel therapeutic strategy for the treatment of multiple sclerosis.