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Dimethyl fumarate improves white matter function following severe hypoperfusion: Involvement of microglia/macrophages
Jill H Fowler1, Jamie McQueen1,2, Philip R Holland1,3
11 Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK.
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 seven 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; 100 mg/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.
Insights
Severe reductions in brain blood flow impair white matter function, increasing microglia/macrophages. The anti-inflammatory drug dimethyl fumarate (DMF) partially improved function and reduced inflammation, suggesting DMF may help treat white matter dysfunction.
Area of Science:
- Neuroscience
- Cerebrovascular Biology
- Neuroinflammation
Background:
- White matter is susceptible to damage from reduced cerebral blood flow.
- Mechanisms may involve microgliosis and pro-inflammatory responses.
Purpose of the Study:
- To investigate the effects of severe cerebral hypoperfusion on white matter function and inflammation.
- To assess the therapeutic potential of dimethyl fumarate (DMF) in mitigating these effects.
Main Methods:
- Male C57Bl/6J mice underwent bilateral common carotid artery stenosis to induce hypoperfusion.
- White matter function was assessed via electrophysiology measuring compound action potentials (CAPs) in the corpus callosum.
- Histological analysis evaluated axonal/myelin pathology and microglia/macrophage density.
Main Results:
- Hypoperfusion significantly impaired white matter function, increasing CAP peak latency and axonal refractoriness, correlated with axonal/myelin damage and increased microglia/macrophages.
- Dimethyl fumarate (DMF) treatment reduced CAP peak latency but not axonal refractoriness.
- DMF treatment normalized microglia/macrophage density in hypoperfused mice, unlike vehicle treatment.
Conclusions:
- Cerebral hypoperfusion causes significant white matter functional impairment and neuroinflammation.
- Increased microglia/macrophages contribute to this functional deficit.
- DMF shows potential in modulating neuroinflammation and improving white matter function following hypoperfusion.
