Fumarate modulates the immune/inflammatory response and rescues nerve cells and neurological function after stroke in rats

Abstract

BackgroundDimethyl fumarate (DMF), working via its metabolite monomethylfumarate (MMF), acts as a potent antioxidant and immunomodulator in animal models of neurologic disease and in patients with multiple sclerosis. These properties and their translational potential led us to investigate whether DMF/MMF could also protect at-risk and/or dying neurons in models of ischemic stroke in vitro and in vivo. Although the antioxidant effects have been partially addressed, the benefits of DMF immunomodulation after ischemic stroke still need to be explored.MethodsIn vitro neuronal culture with oxygen-glucose deprivation and rats with middle cerebral artery occlusion were subjected to DMF/MMF treatment. Live/dead cell counting and LDH assay, as well as behavioral deficits, plasma cytokine assay, western blots, real-time PCR (Q-PCR) and immunofluorescence staining, were used to evaluate the mechanisms and neurological outcomes.ResultsWe found that MMF significantly rescued cortical neurons from oxygen-glucose deprivation (OGD) in culture and suppressed pro-inflammatory cytokines produced by primary mixed neuron/glia cultures subjected to OGD. In rats, DMF treatment significantly decreased infarction volume by nearly 40 % and significantly improved neurobehavioral deficits after middle cerebral artery occlusion (MCAO). In the acute early phase (72 h after MCAO), DMF induced the expression of transcription factor Nrf2 and its downstream mediator HO-1, important for the protection of infarcted cells against oxidative stress. In addition to its antioxidant role, DMF also acted as a potent immunomodulator, reducing the infiltration of neutrophils and T cells and the number of activated microglia/macrophages in the infarct region by more than 50 % by 7–14 days after MCAO. Concomitantly, the levels of potentially harmful pro-inflammatory cytokines were greatly reduced in the plasma and brain and in OGD neuron/glia cultures.ConclusionsWe conclude that DMF is neuroprotective in experimental stroke because of its potent immunomodulatory and antioxidant effects and thus may be useful as a novel therapeutic agent to treat stroke in patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0733-1) contains supplementary material, which is available to authorized users.

Dimethyl fumarate: Regulatory effects on the immune system in the treatment of multiple sclerosis

“…Some evidence suggests that DMF have immunomodulatory effects on innate immune cells in addition to its immunomodulatory properties. Similar effects on the monocytes and macrophages were reported (Lin, Cai, Kostuk, Rosenwasser, & Iacovitti, ; Parodi et al, ). The main effects of DMF on dendritic cells (DCs) are the induction of tolerogenic DCs, inhibition of DC maturation, and modulation of antigen presentation capability (Ghoreschi et al, ; Peng et al, ; Schulze‐Topphoff et al, ).…”

“…DMF acts as a potent immunomodulator in neurologic disease‐related experimental models and patients with MS (Lin et al, ). Significant reduction of microglia and macrophages and preservation of myelin and axonal integrity demonstrated the positive effect of FAE on experimental autoimmune encephalomyelitis (EAE), an animal model mimicking several aspects of MS (Bomprezzi, ).…”

“…In addition, DMF decreases the infiltration of neutrophils (Lin et al, ). Neutrophils originate from the bone marrow and accumulate in the periphery before onset the preclinical phase of EAE (Rumble et al, ).…”

Systemic Factors Trigger Vasculature Cells to Drive Notch Signaling and Neurogenesis in Neural Stem Cells in the Adult Brain

“…Cell cultures were then washed twice with Hanks' balanced saline solution and OGD media (glucose and phenol red‐free DMEM was deoxygenated by gassing with 95% nitrogen and 5% CO 2 for 15 minutes) as described before and in Supporting Information Material and Methods. The time points used in the experiments were selected based on our unpublished empirical data and the literature and MCAO procedure.…”

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

“…Moreover, transgenic mice with a mutant ICE gene developed smaller infarcts, fewer neurological deficits, lower IL-1β levels and decreased DNA fragmentation after transient and permanent middle cerebral artery occlusion [124,125]. Furthermore, many studies testing therapeutics in animal models of AIS correlate declines in IL-1β levels post-drug administration to improved functional and histologic outcomes post-stroke [115,126,127]. Thus, levels of IL-1β and IL-1Ra can be important predictors of the degree of neuroinlammation following ischemic stroke, as increased levels of IL-1β worsened AIS whereas IL-1Ra provided brain protection [114].…”