RESUMO
OBJECTIVE: To describe Japanese macaque encephalomyelitis (JME), a spontaneous inflammatory demyelinating disease occurring in the Oregon National Primate Research Center's (ONPRC) colony of Japanese macaques (JMs, Macaca fuscata). METHODS: JMs with neurologic impairment were removed from the colony, evaluated, and treated with supportive care. Animals were humanely euthanized and their central nervous systems (CNSs) were examined. RESULTS: ONPRC's JM colony was established in 1965 and no cases of JME occurred until 1986. Since 1986, 57 JMs spontaneously developed a disease characterized clinically by paresis of 1 or more limbs, ataxia, or ocular motor paresis. Most animals were humanely euthanized during their initial episode. Three recovered, later relapsed, and were then euthanized. There was no gender predilection and the median age for disease was 4 years. Magnetic resonance imaging of 8 cases of JME revealed multiple gadolinium-enhancing T(1) -weighted hyperintensities in the white matter of the cerebral hemispheres, brainstem, cerebellum, and cervical spinal cord. The CNS of monkeys with JME contained multifocal plaque-like demyelinated lesions of varying ages, including acute and chronic, active demyelinating lesions with macrophages and lymphocytic periventricular infiltrates, and chronic, inactive demyelinated lesions. A previously undescribed gamma-herpesvirus was cultured from acute JME white matter lesions. Cases of JME continue to affect 1% to 3% of the ONPRC colony per year. INTERPRETATION: JME is a unique spontaneous disease in a nonhuman primate that has similarities with multiple sclerosis (MS) and is associated with a novel simian herpesvirus. Elucidating the pathogenesis of JME may shed new light on MS and other human demyelinating diseases.
Assuntos
Encefalomielite/patologia , Encefalomielite/veterinária , Doenças dos Macacos/patologia , Esclerose Múltipla/patologia , Idade de Início , Animais , Ataxia/etiologia , Encéfalo/patologia , Proteínas do Líquido Cefalorraquidiano/metabolismo , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/veterinária , Encefalomielite/líquido cefalorraquidiano , Feminino , Herpesviridae/genética , Herpesviridae/isolamento & purificação , Infecções por Herpesviridae/veterinária , Humanos , Imuno-Histoquímica , Macaca , Imageamento por Ressonância Magnética , Masculino , Doenças dos Macacos/líquido cefalorraquidiano , Paralisia/etiologiaRESUMO
Lipoic acid is a natural antioxidant available as an oral supplement from a number of different manufacturers. Lipoic acid administered subcutaneously is an effective therapy for murine experimental autoimmune encephalomyelitis, a model of multiple sclerosis. The aim of this study was to compare serum lipoic acid levels with oral dosing in patients with multiple sclerosis with serum levels in mice receiving subcutaneous doses of lipoic acid. We performed serum pharmacokinetic studies in patients with multiple sclerosis after a single oral dose of 1200 mg lipoic acid. Patients received one of the three different racemic formulations randomly: tablet (Formulation A) and capsules (Formulations B and C). Mice pharmacokinetic studies were performed with three different subcutaneous doses (20, 50 and 100 mg/kg racemic lipoic acid). The pharmacokinetic parameters included Maximum Serum Concentrations (C(max) in microg/ml) and area under the curve (0-infinity) (AUC ( 0-infinity) in microg*min/ml). We found mean C(max) and AUC (0-infinity) in patients with multiple sclerosis as follows: group A (N = 7) 3.8 +/- 2.6 and 443.1 +/- 283.9; group B (N = 8) 9.9 +/- 4.5 and 745.2 +/- 308.7 and group C (N = 8) 10.3 +/- 3.8 and 848.8 +/- 360.5, respectively. Mean C(max) and AUC (0-infinity) in the mice were: 100 mg/kg lipoic acid: 30.9 +/- 2.9 and 998 +/- 245; 50 mg/kg lipoic acid: 7.6 +/- 1.4 and 223 +/- 20; 20 mg/kg lipoic acid: 2.7 +/- 0.7 and 119 +/- 33. We conclude that patients taking 1200 mg of lipoic acid from two of the three oral formulations achieved serum C(max) and AUC levels comparable to that observed in mice receiving 50 mg/kg subcutaneous dose of lipoic acid, which is a highly therapeutic dose in experimental autoimmune encephalomyelitis. A dose of 1200 mg oral lipoic acid can achieve therapeutic serum levels in patients with multiple sclerosis.
Assuntos
Antioxidantes/farmacocinética , Suplementos Nutricionais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fatores Imunológicos/farmacocinética , Esclerose Múltipla/tratamento farmacológico , Ácido Tióctico/farmacocinética , Administração Oral , Adulto , Idoso , Animais , Antioxidantes/administração & dosagem , Área Sob a Curva , Disponibilidade Biológica , Cápsulas , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/sangue , Injeções Subcutâneas , Masculino , Taxa de Depuração Metabólica , Camundongos , Pessoa de Meia-Idade , Comprimidos , Ácido Tióctico/administração & dosagem , Ácido Tióctico/sangue , Distribuição TecidualRESUMO
BACKGROUND: Lipoic acid, an antioxidant, has beneficial effects in experimental acute optic neuritis and autoimmune encephalomyelitis. Optical coherence tomography can detect retinal nerve fiber layer thinning, representing axonal degeneration, approximately 3-6 months after acute optic neuritis. OBJECTIVE: To determine whether lipoic acid is neuroprotective in acute optic neuritis. METHODS: A single-center, double-blind, randomized, placebo controlled, 24-week trial. Intervention included 6 weeks of once daily lipoic acid (1200 mg) or placebo within 14 days of acute optic neuritis diagnosis. The primary outcome was the mean difference in affected eye retinal nerve fiber layer (RNFL) thickness from baseline to 24 weeks. RESULTS: We enrolled 31 subjects (placebo n=16; lipoic acid n=15; average age 38.6 years (standard deviation (SD) 10.3)). Affected eye mean global RNFL thickness (µm) in the lipoic acid group decreased from 108.47 (SD 26.11) at baseline to 79.31 (SD 19.26) at 24 weeks. The affected eye RNFL in the placebo group decreased from 103.67 (SD 18.04) at baseline to 84.43 (SD 20.94) at 24 weeks. Unaffected eye RNFL thickness did not significantly change in either group over 24 weeks. CONCLUSION: Six weeks of oral lipoic acid supplementation after acute optic neuritis is safe and well tolerated; however, because of insufficient recruitment, we could not conclude that lipoic acid treatment was neuroprotective in acute optic neuritis.
RESUMO
The antioxidant lipoic acid (LA) treats and prevents the animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). In an effort to understand the therapeutic potential of LA in MS, we sought to define the cellular mechanisms that mediate the effects of LA on human natural killer (NK) cells, which are important in innate immunity as the first line of defense against invading pathogens and tumor cells. We discovered that LA stimulates cAMP production in NK cells in a dose-dependent manner. Studies using pharmacological inhibitors and receptor transfection experiments indicate that LA stimulates cAMP production via activation of the EP2 and EP4 prostanoid receptors and adenylyl cyclase. In addition, LA suppressed interleukin (IL)-12/IL-18 induced IFNgamma secretion and cytotoxicity in NK cells. These novel findings suggest that LA may inhibit NK cell function via the cAMP signaling pathway.
Assuntos
Antioxidantes/farmacologia , AMP Cíclico/biossíntese , Interferon gama/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Receptores de Prostaglandina E/efeitos dos fármacos , Ácido Tióctico/farmacologia , Testes Imunológicos de Citotoxicidade , Citotoxicidade Imunológica/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Humanos , Interferon gama/biossíntese , Receptores de Prostaglandina E/metabolismo , Receptores de Prostaglandina E Subtipo EP2 , Receptores de Prostaglandina E Subtipo EP4 , Transdução de Sinais/efeitos dos fármacosRESUMO
Lipoic acid (LA) suppresses and treats murine experimental autoimmune encephalomyelitis (EAE), which models multiple sclerosis. However, the mechanisms by which LA mediates its effects in EAE are only partially known. In the present study, LA (25, 50 and 100 microg/ml) inhibited upregulation of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in tumor necrosis factor-alpha (TNF-alpha) stimulated cultured brain endothelial cells. Immunohistochemical analysis of spinal cords from SJL mice that had received LA (100 mg/kg/day) following immunization to induce EAE exhibited markedly reduced expression of ICAM-1 and VCAM-1 compared with that of EAE mice receiving saline. Co-localization analysis showed that ICAM-1 and VCAM-1 expression increased over endothelial cells (staining positive for von Willebrand factor, vWF) in EAE and that LA decreased the expression levels to that observed in naïve mice. Spinal cords from mice receiving LA had significantly reduced inflammation (decreased CD4 and CD11b staining) as compared to EAE mice that received saline. Overall, our data suggest that the anti-inflammatory effects of LA in EAE may be partly due to inhibition of ICAM-1 and VCAM-1 expression by central nervous system (CNS) endothelial cells.
Assuntos
Inibição de Migração Celular , Regulação para Baixo/efeitos dos fármacos , Encefalomielite Autoimune Experimental/metabolismo , Molécula 1 de Adesão Intercelular , Medula Espinal/metabolismo , Linfócitos T/metabolismo , Ácido Tióctico/farmacologia , Molécula 1 de Adesão de Célula Vascular , Animais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Molécula 1 de Adesão Intercelular/biossíntese , Camundongos , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Ácido Tióctico/uso terapêutico , Molécula 1 de Adesão de Célula Vascular/biossínteseRESUMO
Oxidative injury may be important to the pathogenesis of multiple sclerosis (MS). We tested the antioxidant alpha lipoic acid (ALA) in an experimental murine model of MS, experimental autoimmune encephalomyelitis (EAE). ALA was administered to SJL mice 7 days after immunization with proteolipid protein (PLP) 139-151 peptide. Mice that received 5-100 mg/kg/day of ALA had dose-dependent reductions in their 10-Day Cumulative Disease Scores (10-Day CDS) by 23-100%. Minimal inflammation, demyelination and axonal loss occurred in the spinal cords (SC) of ALA-suppressed mice, and there was a marked reduction in CD3+ T cells and CD11b+ monocyte/macrophage cells within the SC. Mice treated with ALA (100 mg/kg/day) commencing on the first day of clinical EAE had a significant reduction in 10-Day CDS. SC of ALA-treated mice had reduced demyelination and axonal loss and a rapid reduction in CD3+ T cells. In vitro, ALA and its reduced form, dihydrolipoic acid, inhibited the activity of matrix metalloproteinase-9 (MMP-9) in a dose-dependent fashion. ALA is highly effective at suppressing and treating EAE and does so by inhibiting T cell trafficking into the SC, perhaps by acting as a matrix metalloproteinase inhibitor.
Assuntos
Antioxidantes/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Medula Espinal/imunologia , Linfócitos T/imunologia , Ácido Tióctico/uso terapêutico , Doença Aguda , Animais , Antioxidantes/farmacologia , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Encefalomielite Autoimune Experimental/diagnóstico , Encefalomielite Autoimune Experimental/imunologia , Inibidores Enzimáticos/farmacologia , Linfonodos/imunologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Proteína Proteolipídica de Mielina/imunologia , Fragmentos de Peptídeos/imunologia , Prevenção Secundária , Medula Espinal/patologia , Ácido Tióctico/farmacologiaRESUMO
Lipoic acid is an antioxidant that suppresses and treats a model of multiple sclerosis, experimental autoimmune encephalomyelitis. We now demonstrate that treatment of human PBMC and T cell lines with LA downmodulated CD4 expression in a concentration-dependent manner. LA treatment of Con A stimulated PBMC specifically removed CD4 from the T-cell surface, but not CD3. Epitope masking by LA was excluded by using monoclonal antibodies targeting different domains of CD4. Incubation on ice inhibited CD4 removal following LA treatment, suggesting that endocytosis was involved in its downmodulation. LA is in a unique category of compounds that induce CD4 downmodulation by various mechanisms (e.g., gangliosides). We hypothesized that LA might induce dissociation of p56(Lck) from CD4, thus leading to its downmodulation. Immunoblot analyses demonstrated reduced co-precipitation of p56(Lck) from Jurkat T-cells following LA treatment and precipitation of CD4. This unique immunomodulatory effect of LA warrants further investigation.
Assuntos
Antígenos CD4/metabolismo , Leucócitos Mononucleares/metabolismo , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Linfócitos T/metabolismo , Ácido Tióctico/administração & dosagem , Antioxidantes/administração & dosagem , Células Cultivadas , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Humanos , Células Jurkat , Leucócitos Mononucleares/efeitos dos fármacos , Ligação Proteica , Linfócitos T/efeitos dos fármacosRESUMO
We have demonstrated previously the ability of the antioxidant alpha lipoic acid (ALA) to suppress and treat a model of multiple sclerosis (MS), relapsing experimental autoimmune encephalomyelitis (EAE). We describe the effects of ALA and its reduced form, dihydrolipoic acid (DHLA), on the transmigration of human Jurkat T cells across a fibronectin barrier in a transwell system. ALA and DHLA inhibited migration of Jurkat cells in a dose-dependent fashion by 16-75%. ALA and DHLA reduced matrix metalloproteinase-9 (MMP-9) activity by 18-90% in Jurkat cell supernatants. GM6001, a synthetic inhibitor of MMP, reduced Jurkat cell migration, but not as effectively as ALA and DHLA did. Both ALA and DHLA downmodulated the surface expression of the alpha4beta1 integrin (very late activation-4 antigen; VLA-4), which binds fibronectin and its endothelial cell ligand vascular cell adhesion molecule-1 (VCAM-1). Moreover, ALA, but not DHLA, reduced MMP-9-specific mRNA and extracellular MMP-9 from Jurkat cells and their culture supernatants as detected by relative reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. ALA and DHLA inhibited Jurkat cell migration and have different mechanisms for inhibiting MMP-9 activity. These data, coupled with its ability to treat relapsing EAE, suggest that ALA warrants investigation as a therapy for MS.