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A sensitization-free dimethyl fumarate (DMF) pro-drug, isosorbide di-(methyl fumarate) (IDMF), provides a topical treatment candidate for psoriasis [RNA-seq]

ABSTRACT: Dimethyl fumarate (DMF) is an effective oral treatment for psoriasis administered in Europe for nearly 60 years. Its potential, however, has been limited by contact dermatitis that prohibits topical application. This paper characterizes a DMF derivative, isosorbide di-(methyl fumarate) (IDMF), which was designed to have anti-psoriatic effects without skin-sensitizing properties. We show that IDMF exhibits neither genotoxicity nor radiation sensitivity in skin fibroblasts and is non-irritating and non-sensitizing in animal models (rat, rabbit, guinea pig). Microarray analysis of cytokine-stimulated keratinocytes showed that IDMF represses the expression of genes specifically up-regulated in psoriatic skin lesions but not those of other skin diseases. IDMF also down-regulated genes induced by IL-17A and TNF in keratinocytes, as well as predicted targets of NF-κB and the anti-differentiation ncRNA (ANCR). IDMF further stimulated transcription of oxidative stress response genes (NQO1, GPX2, GSR) with stronger Nrf2/ARE activation compared to DMF. Finally, IDMF reduced erythema and scaling while repressing expression of immune response genes in psoriasiform lesions elicited by topical application of imiquimod in mice. These data demonstrate that IDMF exbibits anti-psoriatic activity that is similar or improved compared to DMF, without the harsh skin-sensitizing effects that have prevented topical delivery of the parent molecule.

ORGANISM(S): Mus musculus

PROVIDER: GSE175471 | GEO | 2021/08/22

REPOSITORIES: GEO

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Project description:The fumarate ester dimethyl fumarate (DMF) has been introduced recently for the treatment of relapsing remitting multiple sclerosis (RRMS), a chronic inflammatory condition resulting in neuronal demyelination and axonal loss. The complete mechanism of DMF action is unknown, but involves the depletion of intracellular glutathione and modification of thiols on Kelch-like ECH-associated protein 1 (Keap1), which in turn induces the expression of antioxidant response element genes. Previous work by our laboratory has shown that DMF reacts with a wide range of protein thiols in adipocytes, detected following ester hydrolysis by an antibody recognizing succinated proteins. We proposed that other intracellular thiol residues may also be irreversibly modified by DMF in neurons and astrocytes. DMF treatment of primary rodent neurons and astrocytes, as well as differentiated N1E-115 cells, resulted in the modification of 24 novel target proteins by mass spectrometry. Using this approach, we confirmed the identification and site of modification of the identified proteins, which include cofilin-1, tubulin and collapsin response mediator protein 2 (CRMP2). An in vitro functional assay that measures the ability of cofilin-1 to sever the actin cytoskeleton demonstrated that DMF-modified cofilin-1 loses activity and generates less monomeric actin, potentially inhibiting cofilin’s cytoskeletal remodeling activity; an effect that could be beneficial in the modulation of myelination during RRMS. DMF modification of tubulin did not significantly impact axonal lysosomal trafficking. The oxygen consumption rate of N1E-115 neurons and the levels of proteins related to mitochondrial energy production were only slightly affected by the highest doses of DMF, confirming that DMF treatment does not impair cellular respiratory function. In summary, we demonstrate that in addition to the stimulation of the antioxidant response, DMF resulted in electrophilic modification of novel protein targets that provide new insight on the mechanisms supporting the neuroprotective and re-myelination benefits associated with DMF treatment.

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A sensitization-free dimethyl fumarate (DMF) pro-drug, isosorbide di-(methyl fumarate) (IDMF), provides a topical treatment candidate for psoriasis [RNA-seq]

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