RESUMEN
Mitoxantrone has been approved by the FDA for the treatment of multiple sclerosis (MS). However, the mechanisms by which mitoxantrone modulates MS are largely unknown. Activated astrocytes produce nitric oxide (NO), TNF-α, and IL-1ß, molecules which can be toxic to central nervous system (CNS) cells including oligodendrocytes, thus potentially contributing to the pathology associated with MS. MCP-1 is a chemokine believed to modulate the migration of monocytes to inflammatory lesions present in the CNS of MS patients. IL-12 and IL-23 have been demonstrated to play critical roles in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, by contributing to the development of CD4(+) T cell lineages termed Th1 and Th17, respectively. The current study demonstrates that mitoxantrone inhibits lipopolysachharide (LPS) induction of NO, TNF-α, IL-1ß, and MCP-1 production by primary astrocytes. Mitoxantrone also inhibited IL-12 and IL-23 production by these cells. Furthermore, mitoxantrone suppressed the expression of C-reactive protein (CRP). Finally, we demonstrate that mitoxantrone suppressed LPS induction of NF-κB DNA-binding activity, suggesting a novel mechanism by which mitoxantrone suppresses the expression of proinflammatory molecules. Collectively, these studies demonstrate that mitoxantrone represses astrocyte production of potentially cytotoxic molecules, as well as molecules capable of altering T-cell phenotype. These in vitro studies suggest mechanisms by which mitoxantrone may modulate inflammatory diseases including MS.
Asunto(s)
Antiinflamatorios/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Mitoxantrona/farmacología , Esclerosis Múltiple , Animales , Astrocitos/inmunología , Supervivencia Celular , Células Cultivadas , Ensayo de Cambio de Movilidad Electroforética , Ensayo de Inmunoadsorción Enzimática , Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BLRESUMEN
OBJECTIVE: To compare whole-body fat mass and fat-free mass (FFM) in ambulatory patients with multiple sclerosis (MS) and control subjects without MS. DESIGN: Nonrandomized controlled trial or cross-sectional study. SETTING: An exercise physiology laboratory at a medical school. PARTICIPANTS: Seventeen ambulatory patients with MS and 12 control subjects (all subjects were women). The median Expanded Disability Status Scale (EDSS) score was 4.0 for the individuals with MS. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Whole-body percentage of fat-free mass (%FFM), percentage of body fat (%BF), FFM, and fat mass. RESULTS: A significant difference in age was observed between the groups; thus, age was used as a covariate in the body composition analyses. No significant differences were observed between the groups in %BF: 32.5+/-13.9 and 27.8+/-5.6 (P=.54) for MS and controls, respectively, or %FFM, 67.1+/-14.9 and 71.3+/-12.4 (P=.42) for MS and controls, respectively. For individuals with MS, no significant relation was observed between EDSS score and %BF (P=.24) or between EDSS score and %FFM (P=.24). CONCLUSION: No significant differences were observed in body composition between ambulatory MS patients and controls. Furthermore, the EDSS score was not a significant predictor of %BF or %FFM for people with MS.