Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

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

Authors: Hallel C. Paraiso, Ping-Chang Kuo, Eric T. Curfman, Haley J. Moon, Robert D. Sweazey, Jui-Hung Yen, Fen-Lei Chang, I-Chen Yu

Published in: Journal of Neuroinflammation | Issue 1/2018

Login to get access

Abstract

Background

Systemic 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.

Methods

Primary 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.

Results

DMF 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.

Conclusions

DMF treatment might protect neurons against toxic microenvironments produced by reactive MG and astrocytes associated with systemic inflammation.
Appendix
Available only for authorised users
Literature
1.
Teeling JL, Perry VH. Systemic infection and inflammation in acute CNS injury and chronic neurodegeneration: underlying mechanisms. Neuroscience. 2009;158:1062–73.CrossRefPubMed
2.
3.
Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis. JAMA. 2010;304:443–51.CrossRefPubMed
4.
5.
Yaffe K, Kanaya A, Lindquist K, Simonsick EM, Harris T, Shorr RI, Tylavsky FA, Newman AB. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA. 2004;292:2237–42.CrossRefPubMed
6.
Marsland AL, Gianaros PJ, Abramowitch SM, Manuck SB, Hariri AR. Interleukin-6 covaries inversely with hippocampal grey matter volume in middle-aged adults. Biol Psychiatry. 2008;64:484–90.CrossRefPubMedCentralPubMed
7.
Shemer A, Erny D, Jung S, Prinz M. Microglia plasticity during health and disease: an immunological perspective. Trends Immunol. 2015;36:614–24.CrossRefPubMed
8.
9.
10.
Perry VH, Holmes C. Microglial priming in neurodegenerative disease. Nat Rev Neurol. 2014;10:217–24.CrossRefPubMed
11.
Altmeyer PJ, Matthes U, Pawlak F, Hoffmann K, Frosch PJ, Ruppert P, Wassilew SW, Horn T, Kreysel HW, Lutz G, et al. Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J Am Acad Dermatol. 1994;30:977–81.CrossRefPubMed
12.
Mrowietz U, Asadullah K. Dimethylfumarate for psoriasis: more than a dietary curiosity. Trends Mol Med. 2005;11:43–8.CrossRefPubMed
13.
Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, Yang M, Raghupathi K, Novas M, Sweetser MT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367:1087–97.CrossRefPubMed
14.
Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098–107.CrossRefPubMed
15.
Linker RA, Gold R. Dimethyl fumarate for treatment of multiple sclerosis: mechanism of action, effectiveness, and side effects. Curr Neurol Neurosci Rep. 2013;13:394.CrossRefPubMed
16.
Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X, Buko A, Chollate S, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011;134:678–92.CrossRefPubMed
17.
Scannevin RH, Chollate S, Jung MY, Shackett M, Patel H, Bista P, Zeng W, Ryan S, Yamamoto M, Lukashev M, Rhodes KJ. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther. 2012;341:274–84.CrossRefPubMed
18.
Chen H, Assmann JC, Krenz A, Rahman M, Grimm M, Karsten CM, Kohl J, Offermanns S, Wettschureck N, Schwaninger M. Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate’s protective effect in EAE. J Clin Invest. 2014;124:2188–92.CrossRefPubMedCentralPubMed
19.
Schulze-Topphoff U, Varrin-Doyer M, Pekarek K, Spencer CM, Shetty A, Sagan SA, Cree BA, Sobel RA, Wipke BT, Steinman L, et al. Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2. Proc Natl Acad Sci U S A. 2016;113:4777–82.CrossRefPubMedCentralPubMed
20.
Giannetti P, Politis M, Su P, Turkheimer F, Malik O, Keihaninejad S, Wu K, Reynolds R, Nicholas R, Piccini P. Microglia activation in multiple sclerosis black holes predicts outcome in progressive patients: an in vivo [(11)C](R)-PK11195-PET pilot study. Neurobiol Dis. 2014;65:203–10.CrossRefPubMed
21.
Yu IC, Kuo PC, Yen JH, Paraiso HC, Curfman ET, Hong-Goka BC, Sweazey RD, Chang FL. A combination of three repurposed drugs administered at reperfusion as a promising therapy for postischemic brain injury. Transl Stroke Res. 2017;8:560–77.CrossRefPubMed
22.
23.
Lin R, Cai J, Kostuk EW, Rosenwasser R, Iacovitti L. Fumarate modulates the immune/inflammatory response and rescues nerve cells and neurological function after stroke in rats. J Neuroinflammation. 2016;13:269.CrossRefPubMedCentralPubMed
24.
Yao Y, Miao W, Liu Z, Han W, Shi K, Shen Y, Li H, Liu Q, Fu Y, Huang D, Shi FD. Dimethyl fumarate and monomethyl fumarate promote post-ischemic recovery in mice. Transl Stroke Res. 2016;7:535–47.CrossRefPubMedCentralPubMed
25.
Kuo PC, Yu IC, Scofield BA, Brown DA, Curfman ET, Paraiso HC, Chang FL, Yen JH. 3H-1,2-Dithiole-3-thione as a novel therapeutic agent for the treatment of ischemic stroke through Nrf2 defense pathway. Brain Behav Immun. 2017;62:180–92.CrossRefPubMed
26.
Witte ME, Mahad DJ, Lassmann H, van Horssen J. Mitochondrial dysfunction contributes to neurodegeneration in multiple sclerosis. Trends Mol Med. 2014;20:179–87.CrossRefPubMed
27.
Moore SJ, Deshpande K, Stinnett GS, Seasholtz AF, Murphy GG. Conversion of short-term to long-term memory in the novel object recognition paradigm. Neurobiol Learn Mem. 2013;105:174–85.CrossRefPubMedCentralPubMed
28.
Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Munch AE, Chung WS, Peterson TC, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–7.CrossRefPubMedCentralPubMed
29.
Michell-Robinson MA, Moore CS, Healy LM, Osso LA, Zorko N, Grouza V, Touil H, Poliquin-Lasnier L, Trudelle AM, Giacomini PS, et al. Effects of fumarates on circulating and CNS myeloid cells in multiple sclerosis. Ann Clin Transl Neurol. 2016;3:27–41.CrossRefPubMed
30.
Wilms H, Sievers J, Rickert U, Rostami-Yazdi M, Mrowietz U, Lucius R. Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1beta, TNF-alpha and IL-6 in an in-vitro model of brain inflammation. J Neuroinflammation. 2010;7:30.CrossRefPubMedCentralPubMed
31.
Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8:57–69.CrossRefPubMed
32.
Peng H, Li H, Sheehy A, Cullen P, Allaire N, Scannevin RH. Dimethyl fumarate alters microglia phenotype and protects neurons against proinflammatory toxic microenvironments. J Neuroimmunol. 2016;299:35–44.CrossRefPubMed
33.
Ambrosius B, Faissner S, Guse K, von Lehe M, Grunwald T, Gold R, Grewe B, Chan A. Teriflunomide and monomethylfumarate target HIV-induced neuroinflammation and neurotoxicity. J Neuroinflammation. 2017;14:51.CrossRefPubMedCentralPubMed
34.
Han R, Xiao J, Zhai H, Hao J. Dimethyl fumarate attenuates experimental autoimmune neuritis through the nuclear factor erythroid-derived 2-related factor 2/hemoxygenase-1 pathway by altering the balance of M1/M2 macrophages. J Neuroinflammation. 2016;13:97.CrossRefPubMedCentralPubMed
35.
Krstic D, Madhusudan A, Doehner J, Vogel P, Notter T, Imhof C, Manalastas A, Hilfiker M, Pfister S, Schwerdel C, et al. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J Neuroinflammation. 2012;9:151.CrossRefPubMedCentralPubMed
36.
Pott Godoy MC, Tarelli R, Ferrari CC, Sarchi MI, Pitossi FJ. Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson's disease. Brain. 2008;131:1880–94.CrossRefPubMed
37.
Vezzani A, Maroso M, Balosso S, Sanchez MA, Bartfai T. IL-1 receptor/toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain Behav Immun. 2011;25:1281–9.CrossRefPubMed
38.
Moraes CA, Santos G, de Sampaio e Spohr TC, D'A vila JC, Lima FR, Benjamim CF, Bozza FA, Gomes FC. Activated microglia-induced deficits in excitatory synapses through IL-1beta: implications for cognitive impairment in sepsis. Mol Neurobiol. 2015;52:653–63.CrossRefPubMed
39.
Hein AM, Stasko MR, Matousek SB, Scott-McKean JJ, Maier SF, Olschowka JA, Costa AC, O'Banion MK. Sustained hippocampal IL-1beta overexpression impairs contextual and spatial memory in transgenic mice. Brain Behav Immun. 2010;24:243–53.CrossRefPubMed
40.
Czerniawski J, Guzowski JF. Acute neuroinflammation impairs context discrimination memory and disrupts pattern separation processes in hippocampus. J Neurosci. 2014;34:12470–80.CrossRefPubMedCentralPubMed
41.
Czerniawski J, Miyashita T, Lewandowski G, Guzowski JF. Systemic lipopolysaccharide administration impairs retrieval of context-object discrimination, but not spatial, memory: evidence for selective disruption of specific hippocampus-dependent memory functions during acute neuroinflammation. Brain Behav Immun. 2015;44:159–66.CrossRefPubMed
42.
Brennan MS, Patel H, Allaire N, Thai A, Cullen P, Ryan S, Lukashev M, Bista P, Huang R, Rhodes KJ, Scannevin RH. Pharmacodynamics of dimethyl fumarate are tissue specific and involve NRF2-dependent and -independent mechanisms. Antioxid Redox Signal. 2016;24:1058–71.CrossRefPubMed
43.
Gillard GO, Collette B, Anderson J, Chao J, Scannevin RH, Huss DJ, Fontenot JD. DMF, but not other fumarates, inhibits NF-kappaB activity in vitro in an Nrf2-independent manner. J Neuroimmunol. 2015;283:74–85.CrossRefPubMed
44.
45.
Li W, Khor TO, Xu C, Shen G, Jeong WS, Yu S, Kong AN. Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis. Biochem Pharmacol. 2008;76:1485–9.CrossRefPubMedCentralPubMed
46.
Soares MP, Seldon MP, Gregoire IP, Vassilevskaia T, Berberat PO, Yu J, Tsui TY, Bach FH. Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation. J Immunol. 2004;172:3553–63.CrossRefPubMed
47.
Hwang YJ, Lee EW, Song J, Kim HR, Jun YC, Hwang KA. MafK positively regulates NF-kappaB activity by enhancing CBP-mediated p65 acetylation. Sci Rep. 2013;3:3242.CrossRefPubMedCentralPubMed
48.
Hennessy E, Griffin EW, Cunningham C. Astrocytes are primed by chronic neurodegeneration to produce exaggerated chemokine and cell infiltration responses to acute stimulation with the cytokines IL-1beta and TNF-alpha. J Neurosci. 2015;35:8411–22.CrossRefPubMedCentralPubMed
49.
Parillaud VR, Lornet G, Monnet Y, Privat AL, Haddad AT, Brochard V, Bekaert A, de Chanville CB, Hirsch EC, Combadiere C, et al. Analysis of monocyte infiltration in MPTP mice reveals that microglial CX3CR1 protects against neurotoxic over-induction of monocyte-attracting CCL2 by astrocytes. J Neuroinflammation. 2017;14:60.CrossRefPubMedCentralPubMed
50.
Galloway DA, Williams JB, Moore CS. Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation. Ann Clin Transl Neurol. 2017;4:381–91.CrossRefPubMedCentralPubMed
51.
Vargas MR, Johnson DA, Sirkis DW, Messing A, Johnson JA. Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J Neurosci. 2008;28:13574–81.CrossRefPubMedCentralPubMed
52.
Hennessy E, Gormley S, Lopez-Rodriguez AB, Murray C, Murray C, Cunningham C. Systemic TNF-alpha produces acute cognitive dysfunction and exaggerated sickness behavior when superimposed upon progressive neurodegeneration. Brain Behav Immun. 2017;59:233–44.CrossRefPubMedCentralPubMed
53.
Muccigrosso MM, Ford J, Benner B, Moussa D, Burnsides C, Fenn AM, Popovich PG, Lifshitz J, Walker FR, Eiferman DS, Godbout JP. Cognitive deficits develop 1month after diffuse brain injury and are exaggerated by microglia-associated reactivity to peripheral immune challenge. Brain Behav Immun. 2016;54:95–109.CrossRefPubMedCentralPubMed
54.
Rojo AI, Pajares M, Rada P, Nunez A, Nevado-Holgado AJ, Killik R, Van Leuven F, Ribe E, Lovestone S, Yamamoto M, Cuadrado A. NRF2 deficiency replicates transcriptomic changes in Alzheimer’s patients and worsens APP and TAU pathology. Redox Biol. 2017;13:444–51.CrossRefPubMedCentralPubMed
55.
Branca C, Ferreira E, Nguyen TV, Doyle K, Caccamo A, Oddo S. Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. Hum Mol Genet. 2017;26:4823–35.CrossRefPubMed
56.
Joshi G, Gan KA, Johnson DA, Johnson JA. Increased Alzheimer’s disease-like pathology in the APP/ PS1DeltaE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiol Aging. 2015;36:664–79.CrossRefPubMed
Metadata
Title
Dimethyl fumarate attenuates reactive microglia and long-term memory deficits following systemic immune challenge
Authors
Hallel C. Paraiso
Ping-Chang Kuo
Eric T. Curfman
Haley J. Moon
Robert D. Sweazey
Jui-Hung Yen
Fen-Lei Chang
I-Chen Yu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1125-5

Other articles of this Issue 1/2018

Journal of Neuroinflammation 1/2018 Go to the issue

Research

The atypical RhoGTPase RhoE/Rnd3 is a key molecule to acquire a neuroprotective phenotype in microglia

Research

Impact of nutrition on inflammation, tauopathy, and behavioral outcomes from chronic traumatic encephalopathy

Research

Histamine upregulates the expression of histamine receptors and increases the neuroprotective effect of astrocytes

Research

Benefits of VCE-003.2, a cannabigerol quinone derivative, against inflammation-driven neuronal deterioration in experimental Parkinson’s disease: possible involvement of different binding sites at the PPARγ receptor

Research

Activation of dopamine D1 receptor decreased NLRP3-mediated inflammation in intracerebral hemorrhage mice

Research

Epigenetic impacts of stress priming of the neuroinflammatory response to sarin surrogate in mice: a model of Gulf War illness