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Fumaric Acids Do Not Directly Influence Gene Expression of Neuroprotective Factors in Highly Purified Rodent Astrocytes

1
Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover, Medical School, 30559 Hannover, Germany
2
Department of Neurology, European Medical School, University Oldenburg, 26129 Oldenburg, Germany
3
Department of Neurology, University Clinic Essen, 45147 Essen, Germany
4
Department of Clinical Immunology and Rheumatology, Hannover Medical School, 30559 Hannover, Germany
5
Center for Systems Neuroscience, University of Veterinary Medicine, 30559 Hannover, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Brain Sci. 2019, 9(9), 241; https://doi.org/10.3390/brainsci9090241
Received: 18 August 2019 / Revised: 12 September 2019 / Accepted: 16 September 2019 / Published: 19 September 2019
(This article belongs to the Special Issue Understanding the Molecular Diversity of Astrocytes)
(1) Background: Dimethylfumarate (DMF) has been approved for the treatment of relapsing remitting multiple sclerosis. However, the mode of action of DMF and its assumed active primary metabolite monomethylfumarate (MMF) is still not fully understood. Former reports suggest a neuroprotective effect of DMF mediated via astrocytes by reducing pro-inflammatory activation of these glial cells. We investigated potential direct effects of DMF and MMF on neuroprotective factors like neurotrophic factors and growth factors in astrocytes to elucidate further possible mechanisms of the mode of action of fumaric acids; (2) Methods: highly purified cultures of primary rat astrocytes were pre-treated in vitro with DMF or MMF and incubated with lipopolysaccharides (LPS) or a mixture of interferon gamma (IFN-γ) plus interleukin 1 beta (IL-1β) in order to simulate an inflammatory environment. The gene expression of neuroprotective factors such as neurotrophic factors (nuclear factor E2-related factor 2 (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF)) and growth factors (fibroblast growth factor 2 (FGF2), platelet-derived growth factor subunit A (PDGFa), ciliary neurotrophic factor (CNTF)) as well as cytokines (tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6), IL-1β, inducible nitric oxide synthase (iNOS)) was examined by determining the transcription level with real-time quantitative polymerase chain reaction (qPCR); (3) Results: The stimulation of highly purified astrocytes with either LPS or cytokines changed the expression profile of growth factors and pro- inflammatory factors. However, the expression was not altered by either DMF nor MMF in unstimulated or stimulated astrocytes; (4) Conclusions: There was no direct influence of fumaric acids on neuroprotective factors in highly purified primary rat astrocytes. This suggests that the proposed potential neuroprotective effect of fumaric acid is not mediated by direct stimulation of neurotrophic factors in astrocytes but is rather mediated by other pathways or indirect mechanisms via other glial cells like microglia as previously demonstrated. View Full-Text
Keywords: glia; astrocytes; dimethylfumarate; monomethylfumarate; neuroprotection; growth factors glia; astrocytes; dimethylfumarate; monomethylfumarate; neuroprotection; growth factors
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Pars, K.; Gingele, M.; Kronenberg, J.; Prajeeth, C.K.; Skripuletz, T.; Pul, R.; Jacobs, R.; Gudi, V.; Stangel, M. Fumaric Acids Do Not Directly Influence Gene Expression of Neuroprotective Factors in Highly Purified Rodent Astrocytes. Brain Sci. 2019, 9, 241.

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