Dimethyl Fumarate as the Peripheral Blood Inflammatory Mediators Inhibitor in Prevention of Streptozotocin-Induced Neuroinflammation in Aged Rats

Danuta Wrona; Irena Majkutewicz; Grzegorz Świątek; Joanna Dunacka; Beata Grembecka; Wojciech Glac

doi:10.2147/JIR.S342280

Dimethyl Fumarate as the Peripheral Blood Inflammatory Mediators Inhibitor in Prevention of Streptozotocin-Induced Neuroinflammation in Aged Rats

J Inflamm Res. 2022 Jan 6:15:33-52. doi: 10.2147/JIR.S342280. eCollection 2022.

Authors

Danuta Wrona¹, Irena Majkutewicz¹, Grzegorz Świątek¹, Joanna Dunacka¹, Beata Grembecka¹, Wojciech Glac¹

Affiliation

¹ Department of Animal and Human Physiology, Faculty of Biology, University of Gdansk, Gdansk, 80-308, Poland.

Abstract

Purpose: Intracerebroventricular-(ICV)-streptozotocin-(STZ)-induced neuroinflammation is a model of Alzheimer's disease (AD) compatible with the inflammation hypothesis of ageing ("inflammaging" state). Previously, we observed age-dependent (young vs aged) dimethyl fumarate (DMF)-induced anti-inflammatory and neuroprotective effects in the brain along with improvement in cognitive functions in rats with the ICV-STZ-induced model of AD. To evaluate whether DMF reduces neuroinflammation based on the peripheral inflammatory response inhibition, we determined peripheral inflammatory mediators in young and aged rats with the ICV-STZ-induced AD pathology following DMF therapy.

Materials and methods: Young (4-month-old) and aged (22-month-old) rats were fed with 0.4% DMF rat chow for 21 consecutive days after ICV-STZ (3 mg/ventricle) injections. After behavioral testing, blood and spleens were collected to determine the numbers of leukocytes (WBC), lymphocytes and their subpopulations, haematological parameters, the concanavalin (Con)-A-induced production and plasma concentration of interferon (IFN)-γ, interleukin (IL)-6, IL-10 and corticosterone (COR).

Results: Age-dependent anti-inflammatory effect of the DMF treatment in rats with ICV-STZ injections manifested as decreased peripheral WBC and lymphocyte numbers, including TCD3⁺CD4⁺CD8^-, TCD3⁺CD4^-CD8⁺, B (CD45RA⁺) and NK (161a⁺), in aged rats. Furthermore, DMF lowered the blood and spleen lymphocyte production of pro-inflammatory IFN-γ and IL-6 in young and aged rats, whereas it enhanced the plasma level of anti-inflammatory IL-10 and lymphocyte's ability to produce it in aged rats only. In parallel to changes in peripheral WBC numbers in the model of AD, DMF decreased the red blood cell number, haemoglobin concentration, haematocrit and mean platelet volume in aged, but not young, rats. In contrast to controls, DMF did not influence the COR response in STZ groups.

Conclusion: Besides preventing neuroinflammation, DMF acts on the pro-/anti-inflammatory balance in the periphery and causes an anti-inflammatory shift in T lymphocytes which could contribute to DMF's therapeutic effects in the ICV-STZ-induced model of AD, in particular, in aged rats.

Keywords: inflammaging; inflammation; intracerebroventricular-streptozotocin-induced Alzheimer’s disease model; neurotherapeutics; peripheral immunohaematological parameters.

Grants and funding

This project was partially supported by the grant from the Ministry of Science and Higher Education of Poland for young scientists from the University of Gdansk (538-L124-B145-18) and by funding for statutory R&D activities of the Department of Animal and Human Physiology of the University of Gdansk.