Dimethyl fumarate attenuates reactive microglia and long-term memory deficits following systemic immune challenge

Abstract

BackgroundSystemic inflammation is associated with increased cognitive decline and risk for Alzheimer’s disease. Microglia (MG) activated during systemic inflammation can cause exaggerated neuroinflammatory responses and trigger progressive neurodegeneration. Dimethyl fumarate (DMF) is a FDA-approved therapy for multiple sclerosis. The immunomodulatory and anti-oxidant properties of DMF prompted us to investigate whether DMF has translational potential for the treatment of cognitive impairment associated with systemic inflammation.MethodsPrimary murine MG cultures were stimulated with lipopolysaccharide (LPS) in the absence or presence of DMF. MG cultured from nuclear factor (erythroid-derived 2)-like 2-deficient (Nrf2−/−) mice were used to examine mechanisms of DMF actions. Conditioned media generated from LPS-primed MG were used to treat hippocampal neuron cultures. Adult C57BL/6 and Nrf2−/− mice were subjected to peripheral LPS challenge. Acute neuroinflammation, long-term memory function, and reactive astrogliosis were examined to assess therapeutic effects of DMF.ResultsDMF suppressed inflammatory activation of MG induced by LPS. DMF suppressed NF-κB activity through Nrf2-depedent and Nrf2-independent mechanisms in MG. DMF treatment reduced MG-mediated toxicity towards neurons. DMF suppressed brain-derived inflammatory cytokines in mice following peripheral LPS challenge. The suppressive effect of DMF on neuroinflammation was blunted in Nrf2−/− mice. Importantly, DMF treatment alleviated long-term memory deficits and sustained reactive astrogliosis induced by peripheral LPS challenge. DMF might mitigate neurotoxic astrocytes associated with neuroinflammation.ConclusionsDMF treatment might protect neurons against toxic microenvironments produced by reactive MG and astrocytes associated with systemic inflammation.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1125-5) contains supplementary material, which is available to authorized users.

HYCO-3, a dual CO-releaser/Nrf2 activator, reduces tissue inflammation in mice challenged with lipopolysaccharide

“…Concerning the stimulation of pro-inflammation, we observed that all compounds significantly inhibited the expression of pro-inflammatory genes induced by LPS in all organs of C57BL/6 mice and HYCO-3 did not appear more powerful than the other compounds. Thus, it emerges from these findings that: 1) DMF at 40 mg/kg exerts immunomodulatory function despite its inability to induce classical Nrf2-dependent genes that mediate the salutary effects of Nrf2 activation; this is in line with data showing that DMF equally protected wild type and Nrf2 -/- mice from the development of acute inflammatory autoimmune encephalomyelitis [55] and suppressed inflammatory activation of microglia in Nrf2-dependent and independent manner [60] ; 2) CORM-401, which has been evaluated for the first time in our model of systemic inflammation in vivo , potently inhibits the pro-inflammatory response, possibly also by modulating the recruitment of macrophages in certain organs, such as the brain; 3) the combination of DMF+CORM-401 as separate entities or conjugated in the form of a hybrid (HYCO-3) does not enhance the effect of DMF or CORM-401 alone, which is not surprising since the two compounds already nearly abolished the up-regulation of pro-inflammatory genes. Importantly, and in contrast to the majority of reports where DMF or CO-RMs are given prior to or in correspondence with the initiation of inflammation [55] , [60] , this study demonstrates that administration of DMF or CORM-401 after the initiation of inflammation is still very useful in alleviating the tissue inflammatory responses, broadening the therapeutic applicability of these agents and advancing our understanding of their pharmacological characteristics.…”

Dimethyl Fumarate and Its Esters: A Drug with Broad Clinical Utility?

“…The brain is especially sensitive to perturbations caused by oxidative and/or inflammatory stress. In fact, these factors are central to the pathogenesis of several neurodegenerative diseases including Alzheimer’s disease (AD) [ 33 , 92 ], Parkinson’s disease (PD) [ 93 ], Huntington’s disease (HD) and intracerebral haemorrhage (stroke) [ 94 ]. Concomitantly, these diseases are also underscored by pathological mitochondria and perturbations in energy homeostasis (reviewed in [ 95 , 96 ]).…”

“…By reversing mitochondrial TCA cycle flux, there is novel evidence that FAEs might exert at least a portion of their immunomodulatory action through generating succinyl-carnitine esters or other metabolites as well [ 31 , 32 ]. The collective Nrf2-inducing and immuno-modulatory properties of DMF and other FAEs, have demonstrated therapeutic efficacy across multiple body systems such as the central nervous [ 10 , 33 ], cardiovascular [ 34 , 35 ], gastrointestinal [ 7 , 36 , 37 ], immune [ 5 , 38 ] and integumentary [ 39 , 40 ] systems. Thus, the prospective clinical impact of DMF and its esters is extensive.…”

Myeloid Cells in Multiple Sclerosis

“…DMF reduces neuroinflammation levels and cognitive deficits induced by systemic LPS administration in mice [171]. In EAE, DMF promoted the generation of anti-inflammatory monocytes and decreased macrophage infiltration into the CNS resulting in milder clinical deficits.…”