RESUMO
Multiple Sclerosis (MS) is an autoimmune disorder of the Central Nervous System that has been associated with several environmental factors, such as diet and obesity. The possible link between MS and obesity has become more interesting in recent years since the discovery of the remarkable properties of adipose tissue. Once MS is initiated, obesity can contribute to increased disease severity by negatively influencing disease progress and treatment response, but, also, obesity in early life is highly relevant as a susceptibility factor and causally related risk for late MS development. The aim of this review was to discuss recent evidence about the link between obesity, as a chronic inflammatory state, and the pathogenesis of MS as a chronic autoimmune and inflammatory disease. First, we describe the main cells involved in MS pathogenesis, both from neural tissue and from the immune system, and including a new participant, the adipocyte, focusing on their roles in MS. Second, we concentrate on the role of several adipokines that are able to participate in the mediation of the immune response in MS and on the possible cross talk between the latter. Finally, we explore recent therapy that involves the transplantation of adipocyte precursor cells for the treatment of MS.
Assuntos
Adipocinas/metabolismo , Doenças Autoimunes/complicações , Esclerose Múltipla/complicações , Obesidade/complicações , Adipócitos/citologia , Adiponectina/metabolismo , Tecido Adiposo/patologia , Animais , Astrócitos/citologia , Doenças Autoimunes/metabolismo , Linfócitos T CD8-Positivos/citologia , Fator D do Complemento/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/metabolismo , Humanos , Sistema Imunitário , Inflamação , Interleucina-17/metabolismo , Leptina/metabolismo , Células-Tronco Mesenquimais/citologia , Camundongos , Microglia/patologia , Esclerose Múltipla/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Obesidade/metabolismo , Oligodendroglia/citologia , Prevalência , Resistina/metabolismo , Risco , Células Th1/citologia , Células Th2/citologiaRESUMO
BACKGROUND: Multiple Sclerosis (MS) is an immune-mediated demyelinating disease mainly affecting the Central Nervous System (CNS). 80% of MS patients present the Relapsing-Remitting form (RRMS). Pleiotrophin (PTN), a cytokine previously associated with other autoimmune and neurological diseases, could play a role in the pathophysiology of RRMS due to its neuro and immunomodulatory effect. However, PTN has never been explored in RRMS patients. AIM OF THE STUDY: To determine PTN serum levels in patients with RRMS, treated with Glatiramer acetate (GA) or Interferon-beta (IFN-ß), as well as in non-treated patients and healthy controls as a first attempt to explore PTN in RRMS. METHODS: PTN serum levels were quantified by ELISA in 57 patients and 18 controls. RESULTS: We demonstrated that PTN serum levels are significantly higher in RRMS patients. In IFN-ß treated patients alone, PTN correlated positively with time of disease evolution and time of IFN-ß use and correlated negatively with the MS severity score (MSSS). When comparing groups according to weight status, we observed that PTN is statistically increased in overweight female patients and that weight does not affect male patients. The Area Under the Curve (AUC) of the Receiver Operating Characteristic (ROC) curve analysis was higher for males compared to females. CONCLUSION: PTN serum level is higher in RRMS patients and that is associated with sex, BMI and IFN-ß treatment. Therefore, we propose that PTN could be playing a role in MS. Further studies must be performed to identify the exact role of PTN in this pathology.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Índice de Massa Corporal , Proteínas de Transporte , Citocinas , Feminino , Humanos , Masculino , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológicoRESUMO
L-DOPA is still the drug of choice to treat Parkinson's disease although adverse side effects appear after several years of treatment. These are thought to be the consequence of plastic re-arrangements of the nigrostriatal connections, such as sprouting of the dopaminergic terminals or post-synaptic changes. Pleiotrophin, a trophic factor that we have shown to be up-regulated in the striatum of parkinsonian rats after long-term L-DOPA treatment may play a role in these plastic changes. To determine whether one of the three known pleiotrophin receptors [N-syndecan, receptor protein tyrosine phosphatase type zeta beta (RPTP-zeta/beta) and anaplastic lymphoma kinase] might be implicated in these putative plastic effects, we quantified their expression levels by real-time RT-PCR in the striatum and mesencephalon of rats with partial lesions of the nigrostriatal pathway undergoing L-DOPA treatment. Both pleiotrophin and RPTP-zeta/beta expression was up-regulated in the striatum but not in the mesencephalon of lesioned rats and RPTP-zeta/beta expression was even further increased by L-DOPA. The levels of the RPTP-zeta/beta protein were also increased in the striatum of L-DOPA-treated lesioned rats. Immunofluorescence labeling showed the protein to be constitutively expressed in striatal medium spiny neurons, which are innervated by both the corticostriatal glutamatergic and nigrostriatal dopaminergic systems. RPTP-zeta/beta might therefore be implicated in the plastic changes triggered by L-DOPA treatment and might merit further study as a potential candidate for Parkinon's disease therapy.
Assuntos
Antiparkinsonianos/farmacologia , Corpo Estriado/patologia , Levodopa/farmacologia , Neurônios/efeitos dos fármacos , Transtornos Parkinsonianos/tratamento farmacológico , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/metabolismo , Regulação para Cima/efeitos dos fármacos , Análise de Variância , Animais , Antiparkinsonianos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Interações Medicamentosas , Levodopa/uso terapêutico , Masculino , Neurônios/classificação , Neurônios/metabolismo , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/genéticaRESUMO
Pleiotrophin (PTN) is a secreted growth factor, and also a cytokine, associated with the extracellular matrix, which has recently starting to attract attention as a significant neuromodulator with multiple neuronal functions during development. PTN is expressed in several tissues, where its signals are generally related with cell proliferation, growth, and differentiation by acting through different receptors. In Central Nervous System (CNS), PTN exerts post-developmental neurotrophic and -protective effects, and additionally has been involved in neurodegenerative diseases and neural disorders. Studies in Drosophila shed light on some aspects of the different levels of regulatory control of PTN invertebrate homologs. Specifically in hippocampus, recent evidence from PTN Knock-out (KO) mice involves PTN functioning in learning and memory. In this paper, we summarize, discuss, and contrast the most recent advances and results that lead to proposing a PTN as a neuromodulatory molecule in the CNS, particularly in hippocampus.
RESUMO
The in vitro differentiation of embryonic stem cells into glia has received relatively limited attention to date when compared with the interest in the generation of neurons. We are interested in a particular glial phenotype, the aldynoglia, and their differentiation from multipotential neural precursors (MNP), since this type of glia can promote neuronal regeneration. We constructed cDNA libraries from cultures of purified olfactory ensheathing cells (OEC), an aldynoglia cell type, and MNP to perform subtractive hybridization. As a result, we isolated four genes from the OEC: one tenascin C (Tn-C) isoform, Insulin-like growth factor binding protein 5 (Igfbp-5), cytochrome oxidase subunit I (COX1) and a phosphodiesterase for cyclic nucleotides (CNPase). With the exception of CNPase, these genes are expressed more strongly in the OEC than in the MNP and moreover, the expression of all four is induced when MNP were exposed to OEC conditioned media. The data suggest a role for these genes in MNP differentiation, and their products appear to represent characteristic proteins of the aldynoglia phenotype.
Assuntos
Neuroglia/metabolismo , Neurônios/metabolismo , Células-Tronco/metabolismo , 2',3'-Nucleotídeo Cíclico Fosfodiesterases/genética , 2',3'-Nucleotídeo Cíclico Fosfodiesterases/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Meios de Cultivo Condicionados , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Expressão Gênica , Biblioteca Gênica , Técnicas Genéticas , Proteína Glial Fibrilar Ácida/metabolismo , Imuno-Histoquímica , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores de Fatores de Crescimento , Receptores de Fator de Crescimento Neural/metabolismo , Tenascina/genética , Tenascina/metabolismoRESUMO
Many studies have shown that deficits in olfactory and cognitive functions precede the classical motor symptoms seen in Parkinson's disease (PD) and that olfactory testing may contribute to the early diagnosis of this disorder. Although the primary cause of PD is still unknown, epidemiological studies have revealed that its incidence is increased in consequence of exposure to certain environmental toxins. In this study, most of the impairments presented by C57BL/6 mice infused with a single intranasal (i.n.) administration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1 mg/nostril) were similar to those observed during the early phase of PD, when a moderate loss of nigral dopamine neurons results in olfactory and memory deficits with no major motor impairments. Such infusion decreased the levels of the enzyme tyrosine hydroxylase in the olfactory bulb, striatum, and substantia nigra by means of apoptotic mechanisms, reducing dopamine concentration in different brain structures such as olfactory bulb, striatum, and prefrontal cortex, but not in the hippocampus. These findings reinforce the notion that the olfactory system represents a particularly sensitive route for the transport of neurotoxins into the central nervous system that may be related to the etiology of PD. These results also provide new insights in experimental models of PD, indicating that the i.n. administration of MPTP represents a valuable mouse model for the study of the early stages of PD and for testing new therapeutic strategies to restore sensorial and cognitive processes in PD.
Assuntos
Intoxicação por MPTP , Neurotoxinas/toxicidade , Doença de Parkinson Secundária/induzido quimicamente , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/administração & dosagem , Administração Intranasal , Análise de Variância , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Monoaminas Biogênicas/metabolismo , Química Encefálica/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Inibição Psicológica , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Neuroquímica , Neurotoxinas/administração & dosagem , Transtornos do Olfato/etiologia , Doença de Parkinson Secundária/complicações , Doença de Parkinson Secundária/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Comportamento Social , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
The mammalian central nervous system contains well-defined regions of plasticity in which cells of the aldynoglia phenotype promote neuronal growth and regeneration. Only now are the factors that regulate the production of new cells from multipotential neural precursors (MNP) starting to be identified. We are interested in understanding how differentiation towards the aldynoglia phenotype is controlled, and to study these events we have induced the differentiation of embryonic MNP towards this phenotype in vitro. Accordingly, we have used microarrays to analyze gene expression in three different cell populations: olfactory bulb ensheathing cells (EC), a prototypic aldynoglia cell type; undifferentiated MNP; and MNP differentiated in vitro for 24 hr in EC-conditioned media. The expression profiles identified support the idea that the EC are more closely related to Schwann cells and astrocytes than to oligodendrocytes. Following MNP differentiation, more strongly expressed genes define a neuroglial cell phenotype. RT-PCR confirms that S100a6, Mtmr2, and Col5a were highly expressed by EC, whereas Pou3f3 were more strongly expressed in MNP than in EC, and SafB1 and Mash1 expression were induced in MNP by EC-conditioned media. The profile of gene expression after differentiation suggests that Wnt signaling may be inactivated during this process, while activation of the BMP pathway may be elicited through the BMPr1A. These results provide us with a starting point to study the genes involved in the induction of aldynoglia differentiation from MNP.