Abstract

White matter damage can occur in a variety of neurological diseases where it contributes significantly to impairment of brain function. Dysregulation of ion gradients across membranes is a common phenomenon across many diseases and can be damaging due to increased metabolic demand, oedema and activation of destructive enzyme cascades. Breakdown of ionic gradients can occur under many circumstances. For example, loss of energy supply to ion pumps causes disruption early in stroke progression. Activation of ion channels through voltage or ligand gating contributes greatly to complications such as intracellular calcium overload in many diseases. This thesis investigated the contribution of different mechanisms of ionic alterations to white matter damage in ischaemic stroke and multiple sclerosis as well as to establish potential treatment options. Particular attention was paid to consequences of glutamate receptor activity. Using the oxygen glucose deprivation model of ischaemia, in the mouse brain slice, it was found that ischaemia-induced potassium release is greater in cortical grey than in corpus callosum white matter. This distinction is dependent on release of vesicular glutamate, as demonstrated by abolition by calcium free media and glutamate receptor antagonists. Variation of ischaemia-induced acidification of grey and white matter was also investigated but no difference between the two tissues was found. A new acute model of demyelination was established, using direct application of cuprizone to the isolated mouse optic nerve, and protection afforded by glutamate receptor antagonists was determined. Antagonism of AMPA and NMDA receptors acted in synergy to provide greater protection than block of each alone. This effect may allow treatment at lower concentrations to limit adverse side effects. When applied separately, NMDA receptor antagonists provided more protection than AMPA receptor antagonists, suggesting this channel contributed more to the injury progression. The same combination of glutamate antagonists was then investigated in the OGD model of ischaemic stroke but provided no more protection than AMPA receptor antagonist alone.

Keywords

White matter, Stroke, Multiple Sclerosis, Glutamate, Electrophysiology, Myelin, Potassium

Document Type

Thesis

Publication Date

2021

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