Einfluss einer Interferon-[beta] Therapie auf die Oligodendrozytenvorläuferzellen : Förderung der Regeneration?

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A β-Lactam Antibiotic Dampens Excitotoxic Inflammatory CNS Damage in a Mouse Model of Multiple Sclerosis

In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), impairment of glial “Excitatory Amino Acid Transporters” (EAATs) together with an excess glutamate-release by invading immune cells causes excitotoxic damage of the central nervous system (CNS). In order to identify pathways to dampen excitotoxic inflammatory CNS damage, we assessed the effects of a β-lactam antibiotic, ceftriaxone, reported to enhance expression of glial EAAT2, in “Myelin Oligodendrocyte Glycoprotein” (MOG)-induced EAE. Ceftriaxone profoundly ameliorated the clinical course of murine MOG-induced EAE both under preventive and therapeutic regimens. However, ceftriaxone had impact neither on EAAT2 protein expression levels in several brain areas, nor on the radioactive glutamate uptake capacity in a mixed primary glial cell-culture and the glutamate-induced uptake currents in a mammalian cell line mediated by EAAT2. Moreover, the clinical effect of ceftriaxone was preserved in the presence of the EAAT2-specific transport inhibitor, dihydrokainate, while dihydrokainate alone caused an aggravated EAE course. This demonstrates the need for sufficient glial glutamate uptake upon an excitotoxic autoimmune inflammatory challenge of the CNS and a molecular target of ceftriaxone other than the glutamate transporter. Ceftriaxone treatment indirectly hampered T cell proliferation and proinflammatory INFγ and IL17 secretion through modulation of myelin-antigen presentation by antigen-presenting cells (APCs) e.g. dendritic cells (DCs) and reduced T cell migration into the CNS in vivo. Taken together, we demonstrate, that a β-lactam antibiotic attenuates disease course and severity in a model of autoimmune CNS inflammation. The mechanisms are reduction of T cell activation by modulation of cellular antigen-presentation and impairment of antigen-specific T cell migration into the CNS rather than or modulation of central glutamate homeostasis

Effects of fumaric acids on cuprizone induced central nervous system de- and remyelination in the mouse.

BACKGROUND: Fumaric acid esters (FAE) are a group of compounds which are currently under investigation as an oral treatment for relapsing-remitting multiple sclerosis. One of the suggested modes of action is the potential of FAE to exert a neuroprotective effect. METHODOLOGY/PRINCIPAL FINDINGS: We have investigated the impact of monomethylfumarate (MMF) and dimethylfumaric acid (DMF) on de- and remyelination using the toxic cuprizone model where the blood-brain-barrier remains intact and only scattered T-cells and peripheral macrophages are found in the central nervous system (CNS), thus excluding the influence of immunomodulatory effects on peripheral immune cells. FAE showed marginally accelerated remyelination in the corpus callosum compared to controls. However, we found no differences for demyelination and glial reactions in vivo and no cytoprotective effect on oligodendroglial cells in vitro. In contrast, DMF had a significant inhibitory effect on lipopolysaccharide (LPS) induced nitric oxide burst in microglia and induced apoptosis in peripheral blood mononuclear cells (PBMC). CONCLUSIONS: These results contribute to the understanding of the mechanism of action of fumaric acids. Our data suggest that fumarates have no or only little direct protective effects on oligodendrocytes in this toxic model and may act rather indirectly via the modulation of immune cells

Influence of DMF and MMF on NO production of LPS stimulated microglia.

<p>After stimulation for 24 h with 10 ng/ml LPS a dose dependent decrease of NO production in cells incubated with DMF (5, 10, 50µM/ml) could be observed. All data represent three independent experiments compared to a daily standard curve using known concentrations of sodium nitrite in culture medium. Results are shown as means ± SEM. Significant post hoc effects versus controls (treated with LPS) are indicated by asterisks (*p<0.05, **p<0.01, ***p<0.001). CO: medium control without LPS.</p

Influence of DMF and MMF on de- and remyelination in the cortex.

<p>Cortical myelin was demonstrated by scoring of MBP (A) and PLP (B). In the cortex score of 0 represents complete myelin protein loss, score of 4 represents normal myelin protein amount. Results are shown as means ± SEM.</p

Influence of DMF and MMF on glial reactions during de- and remyelination.

<p>Graphs represent cell numbers of Nogo-A (A), Olig-2 (B), and Mac-3 (D) positive cells in the corpus callosum. In C results of the APP staining to demonstrate axonal damage during cuprizone treatment are shown. Cell numbers are given as cells/mm². Results are shown as means ± SEM.</p

Induction of apoptosis in mouse PBMC by DMF or MMF for 48h as determined with PI (A) and Annexin (B) staining by flow cytometry.

<p>For controls PBMC were treated with 1.0% methanol or with medium alone (CO). Results are shown as means ± SEM. Significant post hoc effects versus controls (treated with methanol) are indicated by asterisks (**p<0.01, ***p<0.001).</p