Dimethyl fumarate improves white matter function following severe hypoperfusion: involvement of microglia/macrophages and inflammatory mediators

Jill H. Fowler, Jamie Mcqueen, Philip Holland, Yasmina Manso Sanz, Martina Marangoni, Fiona Scott, Emma Chisholm, Robert H Scannevin, Giles E. Hardingham, Karen Horsburgh

Research output: Contribution to journalArticlepeer-review

Abstract

The brain’s white matter is highly vulnerable to reductions in cerebral blood flow via mechanisms that may involve elevated microgliosis and pro-inflammatory pathways. In the present study, the effects of severe cerebral hypoperfusion were investigated on white matter function and inflammation. Male C57Bl/6J mice underwent bilateral common carotid artery stenosis and white matter function was assessed at 7 days with electrophysiology in response to evoked compound action potentials (CAPs) in the corpus callosum. The peak latency of CAPs and axonal refractoriness was increased following hypoperfusion, indicating a marked functional impairment in white matter, which was paralleled by axonal and myelin pathology and increased density and numbers of microglia/macrophages. The functional impairment in peak latency was significantly correlated with increased microglia/macrophages. Dimethyl fumarate (DMF; 100mg/kg), a drug with anti-inflammatory properties, was found to reduce peak latency but not axonal refractoriness. DMF had no effect on hypoperfusion-induced axonal and myelin pathology. The density of microglia/macrophages was significantly increased in vehicle treated hypoperfused- mice whereas DMF treated hypoperfused- mice had similar levels to that of sham treated mice. The study suggests that increased microglia/macrophages following cerebral hypoperfusion contributes to the functional impairment in white matter that may be amenable to modulation by DMF.
Original languageEnglish
Pages (from-to)1354-1370
JournalJournal of Cerebral Blood Flow and Metabolism
Volume38
Issue number8
Early online date13 Jun 2017
DOIs
Publication statusPublished - 1 Aug 2018

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