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Differential neuroprotective and anti-inflammatory effects of dimethyl fumarate, monomethyl fumarate and cannabidiol in neurons and microglia [Mouse]

ABSTRACT: Differential neuroprotective and anti-inflammatory effects of dimethyl fumarate, monomethyl fumarate and cannabidiol in neurons and microglia [Mouse]

PROVIDER: PRJNA1148203 | ENA |

REPOSITORIES: ENA

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Differential neuroprotective and anti-inflammatory effects of dimethyl fumarate, monomethyl fumarate and cannabidiol in neurons and microglia

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Differential neuroprotective and anti-inflammatory effects of dimethyl fumarate, monomethyl fumarate and cannabidiol in neurons and microglia [Mouse]

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Chemical proteomic map of dimethyl fumarate-sensitive cysteines in primary human T cells

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Expression data of renal cancer cell treated with Oncolytic virus VSVd51 and Fumaric acid esters such as Dimethyl fumarate

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Transcriptomic analysis of fumarate compounds identifies unique effects of isosorbide di-(methyl fumarate) on NRF2, NF-kappaB and IRF1 pathway genes

Project description:Dimethyl fumarate (DMF) has emerged as first-line therapy for relapsing-remitting multiple scle-rosis (RRMS). This treatment, however, has been limited by adverse effects, which has prompted development of novel derivatives with improved tolerability. We compared effects of fumarates on gene expression in astrocytes. Our analysis included diroximel fumarate (DRF) and its metabolite monomethyl fumarate (MMF), along with a novel compound isosorbide di-(methyl fumarate) (IDMF). Treatment with IDMF resulted in the largest number of differentially expressed genes. The effects of DRF and MMF were consistent with NRF2 activation and NF-kappaB inhibition, respectively. IDMF responses, however, were concordant with both NRF2 activation and NF-kappaB inhibition, and we confirmed IDMF-mediated NF-kappaB inhibition using a reporter assay. IDMF also down-regulated IRF1 expression and IDMF-decreased gene promoters were enriched with IRF1 recognition se-quences. Genes altered by each fumarate overlapped significantly with those near loci from MS genetic association studies, but IDMF had the strongest overall effect on MS-associated genes. These results show that next-generation fumarates such as DRF and IDMF have effects differing from those of the MMF metabolite. Our findings support a model in which IDMF attenuates oxidative stress via NRF2 activation, with suppression of NF-kappaB and IRF1 contributing to mitigation of in-flammation and pyroptosis.

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