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

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

Research output: Contribution to journalArticle

13 Scopus citations

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.

Original languageEnglish (US)
Article number100
JournalJournal of Neuroinflammation
Volume15
Issue number1
DOIs
StatePublished - Mar 29 2018

Keywords

  • Astrocytes
  • Cognitive impairment
  • Dimethyl fumarate
  • Microglia
  • Neuroinflammation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

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