Pre-clinical Targets for Ischemic Brain Injury

Abstract

Stroke is the second most common cause of disability worldwide, and 87% of strokes result from a blockage in the cerebral blood flow which results in ischemia. Injury to the myelinated axons located in white matter is observed in ischemic injuries but is generally underappreciated. Research has shown that there is extensive vesicular glutamate release during ischemia, causing excitotoxic injury to oligodendrocytes, resulting in demyelination. Glutamate receptor antagonists have been trialled in stroke patients but fall short due to adverse side effects from high dose preparations. Stroke is largely a disease of ageing, and may occur in the presence of other diseases, such as primary age related tauopathy. Tauopathy causes demyelination/remyelination of white matter axons, potentially rendering them more susceptible to ischemic insult. This thesis has used a novel ex vivo electrophysiological model of white matter focal ischemia to analyse the neuroprotective effects that low dose glutamate receptor antagonists have for the treatment of ischemic injury. Additionally, the response of white matter to ischemic insult in the presence of tauopathy was studied using this model. It was found that targeting glutamate receptors with a low concentration of these drugs improves the functional recovery of white matter axons following oxygen glucose depravation. It was also shown that tauopathy increases the vulnerability of the white matter to ischemic insult. The tMCAO model of focal cerebral ischemia was also utilised for electron microscopy studies to test the efficacy of experimental glutamate receptor antagonists. I have shown that prophylaxis using experimental glutamate receptor antagonists reduces the pathology observed in the axon diameter, myelin thickness and G-Ratio of myelinated white matter axons as a consequence of ischemia, as well as reducing axonal and myelinic injury. This study highlights the relevance of the excitotoxic injury mechanisms that occur in the white matter during ischemia, offering an insight as to the clinical utility of glutamate receptor antagonism as a possible treatment paradigm for ischemic brain injuries.