Dimethyl fumarate (DMF) is an antioxidative and anti-inflammatory drug approved for treatment of multiple sclerosis and psoriasis; however, beneficial effects of DMF have also been found in other inflammatory diseases and cancers. DMF is a prodrug that is immediately hydrolysed to monomethyl fumarate (MMF) in vivo. Both fumarates activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, and Nrf2 is a key transcription factor of the antioxidant response. The immunosuppressive and anti-inflammatory actions of DMF occur through several mechanisms: via inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and by downregulation of aerobic glycolysis and pyroptosis in activated myeloid and lymphoid cells. MMF is also an agonist of hydroxycarboxylic acid receptor 2 (HCAR2). Differences in the strength of effects and mechanisms of action of both fumarates are discussed. The aim of this review was to analyse and compare the neuroprotective, antioxidative and anti-inflammatory effects of DMF and its active metabolite, MMF, in cellular (in vitro) and animal models of neurodegenerative diseases (NDs), other than multiple sclerosis. There are more than twenty studies that currently represent this field. Most of the studies are concerned with cellular or animal models of Alzheimer's disease (AD) and Parkinson's disease (PD), one utilized a mouse model of Huntington's disease (HD) and one clinical trial was carried out with amyotrophic lateral sclerosis (ALS) patients. The discrepancies in the results of the various studies are discussed, and issues requiring further research have been identified.

Deep brain stimulation of the subthalamic nucleus (DBS-STN) is an effective treatment for advanced motor symptoms of Parkinson’s disease (PD). Recently, a connection between the limbic part of the STN and side effects of DBS-STN has been increasingly recognized. Animal studies have shown that DBS-STN influences behavior and provokes neurochemical changes in regions of the limbic system. Some of these regions, which are activated during DBS-STN, are involved in neuroimmunomodulation. The therapeutic effects of DBS-STN in PD treatment are clear, but the influence of DBS-STN on peripheral immunity has not been reported so far. In this study, we examined the effects of unilateral DBS-STN applied in male Wistar rats with 6-hydroxydopamine PD model (DBS-6OHDA) and rats without nigral dopamine depletion (DBS) on corticosterone (CORT) plasma concentration, blood natural killer cell cytotoxicity (NKCC), leukocyte numbers, lymphocyte population and apoptosis numbers, plasma interferon gamma (IFN-γ), interleukin 6 (IL-6), and tumor necrosis factor (TNF-α) concentration. The same peripheral immune parameters we measured also in non-stimulated rats with PD model (6OHDA). We observed peripheral immunity changes related to PD model. The NKCC and percentage of T cytotoxic lymphocytes were enhanced, while the level of lymphocyte apoptosis was down regulated in 6OHDA and DBS-6OHDA groups. After DBS-STN (DBS-6OHDA and DBS groups), the plasma CORT and TNF-α were elevated, the number of NK cells and percentage of apoptosis were increased, while the number of B lymphocytes was decreased. We also found, changes in plasma IFN-γ and IL-6 levels in all the groups. These results suggest potential peripheral immunomodulative effects of DBS-STN in the rat model of PD. However, further studies are necessary to explain these findings and their clinical implication.

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.