SEVERE CEREBRAL HYPOPERFUSION INDUCES A DEFICIT IN WHITE MATTER FUNCTION THAT IS ATTENUATED BY MODULATING MICROGLIA WITH DIMETHYL FUMARATE

Abstract

Chronic cerebral hypoperfusion contributes to age-related cognitive decline and dementia such as Alzheimer's disease. The causative link is not yet defined but is proposed to involve damage to the brain's white matter mediated by oxidative stress and inflammation. Dimethyl fumarate (DMF) is an anti-inflammatory drug which acts in part by activating Nrf2-signalling, a master regulator of anti-oxidant and anti-inflammatory pathways. In the present study, the effects of severe cerebral hypoperfusion and DMF administration 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. DMF (100mg/kg) or vehicle was administered twice daily by oral gavage. White matter structural and inflammatory alterations were assessed using immunohistochemistry, and cytokine/chemokine levels were assessed with inflammatory-related protein multiplex. The peak latency of CAPs and axonal refractoriness was increased in the corpus callosum in response to hypoperfusion, indicating a marked functional impairment in white matter, which was paralleled by axonal and myelin pathology. The functional impairment in peak latency was significantly correlated with increased microglial numbers in response to hypoperfusion. Dimethyl fumarate was found to ameliorate the functional deficits in peak latency but not axonal refractoriness. DMF had no effect on hypoperfusion-induced axonal and myelin pathology. Hypoperfusion decreased levels of mature oligodendrocytes and increased levels of immature oligodendrocytes, however these were unaffected by DMF treatment. The density of microglia was significantly increased after hypoperfusion whereas DMF treated mice had similar levels to that of vehicle treated mice, indicating that DMF reduced microgliosis. Chemokine and growth factor molecules were increased in response to severe hypoperfusion and their levels were further modulated by DMF. The study suggests that microglial activation following severe cerebral hypoperfusion contributes to the functional impairment in white matter and that DMF, by reducing microglia, may be of potential therapeutic benefit in cerebral vascular disease. We are currently investigating the therapeutic potential of boosting Nrf2-signalling pathway to prevent neurodegeneration caused by cerebral hypoperfusion using transgenic and novel pharmacological approaches.