Abstract
BackgroundBrain inflammation plays a central role in multiple sclerosis (MS). Dimethylfumarate (DMF), the main ingredient of an oral formulation of fumaric acid esters with proven therapeutic efficacy in psoriasis, has recently been found to ameliorate the course of relapsing-remitting MS. Glial cells are the effector cells of neuroinflammation; however, little is known of the effect of DMF on microglia and astrocytes. The purpose of this study was to use an established in vitro model of brain inflammation to determine if DMF modulates the release of neurotoxic molecules from microglia and astrocytes, thus inhibiting glial inflammation.MethodsPrimary microglial and astrocytic cell cultures were prepared from cerebral cortices of neonatal rats. The control cells were treated with LPS, an accepted inducer of pro-inflammatory properties in glial cells, and the experimental groups with LPS and DMF in different concentrations. After stimulation/incubation, the generation of nitric oxide (NO) in the cell culture supernatants was determined by measuring nitrite accumulation in the medium using Griess reagent. After 6 hours of treatment RT-PCR was used to determine transcription levels of iNOS, IL-1β, IL-6 and TNF-α mRNA in microglial and astrocytic cell cultures initially treated with DMF, followed after 30 min by LPS treatment. Moreover, we investigated possible involvement of the ERK and Nrf-2 transduction pathway in microglia using western blot analysis.ResultsPretreatment with DMF decreased synthesis of the proinflammatory mediators iNOS, TNF-α, IL-1β and IL-6 at the RNA level in activated microglia and astrocytes in vitro, associated with a decrease in ERK phosphorylation in microglia.ConclusionsCollectively, these results suggest that the neuroprotective effects of DMF may be in part functionally attributable to the compound's ability to inhibit expression of multiple neuroinflammatory mediators in brain of MS patients.
Highlights
Brain inflammation plays a central role in multiple sclerosis (MS)
There are only few experimental data available concerning DMF-mediated influences on the glial - especially microglial - environment in the CNS. This could be of interest because part of the effect could be mediated via interference with proinflammatory microglia cell functions: In multiple sclerosis infiltration of T cells into the nervous system initiates a complex immunological cascade consisting of epitope spreading, which triggers new attacks, and activation of the innate immune system which leads to chronic inflammation
Dimethylfumarate reduces mRNA levels of the proinflammatory cytokines IL-1β, IL-6 and TNF-α in microglia To determine if DMF suppresses the expression of IL-1β, IL-6 and TNF-α, real-time RT-PCR analysis was done
Summary
Brain inflammation plays a central role in multiple sclerosis (MS). Dimethylfumarate (DMF), the main ingredient of an oral formulation of fumaric acid esters with proven therapeutic efficacy in psoriasis, has recently been found to ameliorate the course of relapsing-remitting MS. This could be of interest because part of the effect could be mediated via interference with proinflammatory microglia cell functions: In multiple sclerosis infiltration of T cells into the nervous system initiates a complex immunological cascade consisting of epitope spreading, which triggers new attacks, and activation of the innate immune system (e.g. microglia, dendritic cells) which leads to chronic inflammation. The cells become rapidly activated in response to injury or in the presence of pathogens and - like other tissue macrophages in the first line of host defense - play a pivotal role as phagocytic, antigen-presenting cells It is this efficient defensive action that makes them potentially neurotoxic cells. NO reacts with superoxide anion to generate peroxynitrite, a highly reactive molecule capable of oxidizing proteins, lipids and DNA; and which mediates microglial toxicity to oligodendrocytes [14] NO can trigger immune cascades that further enhance inflammatory-mediated CNS damage: Increased concentrations of NO can lead to enhanced expression of chemokine
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