Acute, Low-Grade Inflammation elevates White Matter Sensitivity to Ischaemia

Ischaemic brain injuries, including ischaemic stroke, are highly prevalent neurological diseases. Acute, low-grade inflammation, often resulting from peripheral infection, has emerged as a risk factor. White matter axons, and their supporting glia, are susceptible to both ischaemic and neuroinflammatory injury. The mechanisms behind ischaemic injury in white matter are well established. However, the white matter response to acute, low-grade inflammation, and how this can interact with co-morbidities such as cerebral ischaemia, are yet to be examined. This thesis evaluated the response of white matter to acute, low-grade inflammation and the downstream effects this had on its sensitivity to ischaemia. <br/><br/>Here, I used isolated ex vivo white matter tracts to evaluate both the functional, cellular and sub-cellular response to both ischaemic and acute, low-grade neuroinflammatory insults. Ex vivo modelling showed that white matter tolerates acute, low-grade inflammation, with limited microglial activation but no axo-myelinic damage. However, acute, low-grade inflammation elevated stress to oligodendrocytes which, when put under ischaemic conditions, impaired their ability to maintain healthy myelin. This increased axo-myelinic damage causing an elevated loss in white matter function. I subsequently used a model of microglial depletion to show that the elevated stress to oligodendrocytes was caused by microglia and dampening the microglial response with the clinically available drug minocycline eliminated the elevated white matter sensitivity to ischaemia following acute, low-grade inflammation. <br/>This study therefore identified that the increase of white matter sensitivity to ischaemia caused by acute, low-grade neuroinflammation is a mechanism for understanding why those with acute inflammatory conditions are more prone to ischaemic brain injuries, providing evidence that microglial activation is a clinically targetable mechanism to reduce this risk. <br/>

Author dc:creator

• Mellor, Alex

Contributors dc:contributor

• Robert Fern, Vehid Salih

Language dc:language

eng

Repository record dc:identifier

https://pearl.plymouth.ac.uk/pms-theses/62

OAI identifier oai:identifier

oai:pearl.plymouth.ac.uk:pms-theses-1061