Refereed journal article or data article (A1)

Dimethyl fumarate decreases short-term but not long-term inflammation in a focal EAE model of neuroinflammation




List of Authors: Vainio SK, Dickens AM, Matilainen M, Lopez-Picon FR, Aarnio R, Eskola O, Solin O, Anthony DC, Rinne JO, Airas L, Haaparanta-Solin M

Publisher: SPRINGER

Publication year: 2022

Journal: EJNMMI Research

Journal name in source: EJNMMI RESEARCH

Journal acronym: EJNMMI RES

Volume number: 12

Number of pages: 11

ISSN: 2191-219X

DOI: http://dx.doi.org/10.1186/s13550-022-00878-y

URL: https://ejnmmires.springeropen.com/articles/10.1186/s13550-022-00878-y

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/174785721


Abstract

Background

Dimethyl fumarate (DMF) is an oral immunomodulatory drug used in the treatment of autoimmune diseases. Here, we sought to study whether the effect of DMF can be detected using positron emission tomography (PET) targeting the 18-kDa translocator protein (TSPO) in the focal delayed-type hypersensitivity rat model of multiple sclerosis (fDTH-EAE). The rats were treated orally twice daily from lesion activation (day 0) with either vehicle (tap water with 0.08% Methocel, 200 mu L; control group n = 4 (3 after week four)) or 15 mg/kg DMF (n = 4) in 0.08% aqueous Methocel (200 mu L) for 8 weeks. The animals were imaged by PET using the TSPO tracer [F-18]GE-180 in weeks 0, 1, 2, 4, 8, and 18 following lesion activation, and the non-displaceable binding potential (BPND) was calculated. Immunohistochemical staining for Iba1, CD4, and CD8 was performed in week 18, and in separate cohorts of animals, following 2 or 4 weeks of treatment.

Results

Using the fDTH-EAE model, DMF reduced the [F-18]GE-180 BPND in the DMF-treated animals compared to control animals after 1 week of treatment (two-tailed unpaired t test, p = 0.031), but not in weeks 2, 4, 8, or 18 when imaged in vivo by PET. Immunostaining for Iba1 showed that DMF had no effect on the perilesional volume or the core lesion volume after 2 or 4 weeks of treatment, or at 18 weeks. However, the optical density (OD) measurements of CD4(+) staining showed reduced OD in the lesions of the treated rats.

Conclusions

DMF reduced the microglial activation in the fDTH-EAE model after 1 week of treatment, as detected by PET imaging of the TSPO ligand [F-18]GE-180. However, over an extended time course, reduced microglial activation was not observed using [F-18]GE-180 or by immunohistochemistry for Iba1(+) microglia/macrophages. Additionally, DMF did affect the infiltration of CD4(+) and CD8(+) T-lymphocytes at the fDTH-EAE lesion.


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Last updated on 2022-14-04 at 15:42