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

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.

Heterogeneity of microglia and their differential roles in white matter pathology

“…100 Treatment of dimethyl fumarate, a drug known to suppress microglial inflammation, to mice with severe brain hypoperfusion resulted in modest decrease in the number of inflammatory microglia and macrophages and improved functional impairment in the white matter. 101 Moreover, in rat TBI model, rats co-treated with minocycline and N-acetylcysteine showed altered ratio of pro-inflammatory vs immuno-regulatory population of microglia along with increased remyelination and improved cognition and memory. 14 Overall, these studies support the idea that directly targeting and converting microglial subtypes could be a novel and efficient therapy for various white matter diseases.…”

“…Similarly, treatment of VK‐28 (5‐[4‐(2‐hydroxyethyl) piperazine‐1‐ylmethyl]‐quinoline‐8‐ol), a brain‐permeable iron chelator to intracerebral hemorrhage model of mice, polarized microglia to immuno‐regulatory subtype and deceased white matter injury . Treatment of dimethyl fumarate, a drug known to suppress microglial inflammation, to mice with severe brain hypoperfusion resulted in modest decrease in the number of inflammatory microglia and macrophages and improved functional impairment in the white matter . Moreover, in rat TBI model, rats co‐treated with minocycline and N‐acetylcysteine showed altered ratio of pro‐inflammatory vs immuno‐regulatory population of microglia along with increased remyelination and improved cognition and memory .…”

Melatonin protects against ischemic stroke by modulating microglia/macrophage polarization toward anti‐inflammatory phenotype through STAT3 pathway

“…In vivo and vitro studies revealed that inhibiting pro‐inflammatory microglia phenotype and/or stimulating anti‐inflammatory microglia state were neuroprotective . For example, some drugs, including ginkgolide B, malibatol A, thiamet G, baicalein, isosteviol sodium, curcumin, oxytocin, and dimethyl fumarate have been reported to protect against brain injury through regulating microglia/macrophage polarization and inflammatory responses in experimental models of brain ischemia or hypoperfusion. Some physiological factors, such as hypothermia, also altered microglia/macrophage phenotype.…”

Distinctive functional deficiencies in axonal conduction associated with two forms of cerebral white matter injury

“…Compound action potentials (CAPs) have been widely used to investigate the functional alteration of nerve fibers caused by brain injury or WM degeneration . Based on previous research, there are typically two types of phase peaks in CAPs traces .…”