RESUMO
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by inflammation, but also degenerative changes. Besides neurological deficits, the rate of affective disorders such as depression and anxiety is at least six fold increased. Many aspects of MS can be mimicked in the animal model of myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (MOG-EAE). Here we investigate behavioral changes in C57BL/6 mice suffering from mild MOG-EAE. In the later phase of the disease, mice were subjected to behavioral tests including the light-dark-box (LD Box), the acoustic startle response (SR) with a pre-pulse inhibition protocol as well as the learned helplessness (LH) paradigm. Behavioral data were correlated with the motor performance in an open field and rotarod test (RR). In the RR and open field, there was no significant difference in the motor performance between controls and mice suffering from mild MOG-EAE. Yet EAE mice displayed an increased anxiety-like behavior with a 23% reduction of the time spent in the bright compartment of the LD Box as well as an increased SR. In the LH paradigm, mice suffering from MOG-EAE were twice as much prone to depressive-like behavior. These changes correlate with an increase of hippocampal tissue tumor necrosis factor alpha levels and neuronal loss in the hippocampus. Modulation of monoaminergic transmission by chronic application of the antidepressant amitriptyline resulted in a decreased startle reaction and increased hippocampal norepinephrine levels. These data imply that chronic inflammation in the CNS may impact on emotional responses in rodent models of anxiety.
Assuntos
Ansiedade/etiologia , Inflamação/complicações , Inflamação/etiologia , Esclerose Múltipla/complicações , Estimulação Acústica/efeitos adversos , Amitriptilina/uso terapêutico , Análise de Variância , Animais , Antidepressivos Tricíclicos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/patologia , Sistema Nervoso Central/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Citocinas/metabolismo , Adaptação à Escuridão/efeitos dos fármacos , Adaptação à Escuridão/fisiologia , Doenças Desmielinizantes/etiologia , Depressão/etiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glicoproteínas/efeitos adversos , Desamparo Aprendido , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Esclerose Múltipla/induzido quimicamente , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/efeitos adversos , Toxina Pertussis/efeitos adversos , Fosfopiruvato Hidratase/metabolismo , Psicoacústica , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Teste de Desempenho do Rota-Rod/métodos , Técnicas Estereotáxicas , Fatores de TempoRESUMO
Oxidized phospholipids (Ox-PLs) are generated in abundance at sites of inflammation. Recent studies have indicated that Ox-PLs may also exhibit anti-inflammatory activities. In this study, we investigated the beneficial effect of VB-201, a pure synthetic Ox-PL analog that we synthesized, on the development of a central nervous system (CNS) autoimmune inflammatory disease, in vivo. Oral administration of VB-201 ameliorated the severity of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) peptide MOG35-55, and restrained the encephalogenicity of MOG35-55-specific T-cells. Our data presents a novel prospect for the role of Ox-PL analogs in CNS inflammatory diseases.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Encefalite/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Glicerilfosforilcolina/uso terapêutico , Animais , Células da Medula Óssea/efeitos dos fármacos , Bromodesoxiuridina/metabolismo , Antígenos CD4/metabolismo , Diferenciação Celular/efeitos dos fármacos , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Modelos Animais de Doenças , Interações Medicamentosas , Encefalite/etiologia , Encefalite/imunologia , Encefalomielite Autoimune Experimental/complicações , Encefalomielite Autoimune Experimental/etiologia , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Fatores de Transcrição Forkhead/metabolismo , Adjuvante de Freund/efeitos adversos , Glicerilfosforilcolina/química , Glicerilfosforilcolina/farmacologia , Glicoproteínas/efeitos adversos , Ionomicina/farmacologia , Ionóforos/farmacologia , Linfonodos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/efeitos adversos , Toxina Pertussis/efeitos adversos , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Ácidos Polimetacrílicos/farmacologia , Índice de Gravidade de Doença , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Fatores de TempoRESUMO
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that leads to an inflammatory demyelination, axonal damage, and progressive neurologic disability that affects approximately 2.5 million people worldwide. The aim of the present research was to test the therapeutic effect of Aloe vera in experimental model of MS. All experiments were conducted on C57BL/6 male mice aged 6-8 weeks. To induce the experimental autoimmune encephalomyelitis (EAE), 250 microg of the myelin oligodendrocyte glycoprotein 35-55 peptide emulsified in complete freund's adjuvant was injected subcutaneously on day 0 over two flank areas. In addition, 200 ng of pertussis toxin in 100 microL phosphate buffered saline was injected intraperitoneally on days 0 and 2. The therapeutic protocol was carried out intragastrically using 120 mg/kg/day Aloe vera from 7 days before to 21 days after EAE induction. The mice were killed 21 days after EAE induction. The brains of mice were removed for histological analysis and their isolated splenocytes were cultured. The results indicated that treatment with Aloe vera caused a significant reduction in severity of the disease in experimental model of MS. Histological analysis showed 3 +/- 2 plaques in Aloe vera-treated mice compared with 5 +/- 1 plaques in control group. The density of mononuclear infiltration in the CNS of Aloe vera-treated mice (500 +/- 200) was significantly less in comparison to 700 +/- 185 cells in control group. Moreover, the serum level of nitric oxide in treatment group was significantly less than control animals. The level of interferon-gamma in cell culture supernatant of treated mice splenocytes was lower than control group, whereas decrease in serum level of interleukin-10 in treatment group was not significant in comparison with control mice. These data indicate that Aloe vera therapy can attenuate the disease progression in experimental model of MS.