A model of Endothelin-1-mediated focal ischemia in the mouse forelimb motor cortex

Roome, R. Brian (2013) A model of Endothelin-1-mediated focal ischemia in the mouse forelimb motor cortex. Masters thesis, Memorial University of Newfoundland.

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Abstract

Ischemic stroke is a debilitating medical event with the majority of sufferers experiencing long-term disability and motor impairments. While front line treatment such as anti-embolic medication and rehabilitation can improve the condition, many individuals remain significantly disabled. Experimental therapies involving genetic interventions hold potential for treatment of ischemic stroke, but many therapies go untested due to a lack of small cortical ischemic injury mode ls in the mouse. Models of ischemic stroke should be small, reproducible and produce measurable behavioural deficits in order to see recovery after therapy. Additionally, the injury should avoid damage to neural precursor cells (NPCs) which are often targeted by genetic approaches to modify their survivability and plasticity post stroke. This highlights the demand for a small cortical ischemic injury model in the mouse, where transgenic technologies can be used to their full potential. Existing models of ischemic injury, such as middle cerebral artery occlusion (MCAO) produce large amounts of ischemic damage, but may prove more difficult to regenerate and/or eliminate behavioural deficits post-stroke. Endothelin-1 (ET-1), a potent vasoconstrictive peptide, was used to induce ischemia in the mouse cortex. ET- 1 injected into the mouse cortex produced a small but significant infarct. To determine whether ET-1-induced infarcts could produce behavioural deficits, injections were targeted to the mouse forelimb motor cortex (FMC) and the amount of infarct encompassing the FMC was correlated with behavioural deficits. To analyze this, two-dimensional topological maps of cortical infarct depth were created and the deeper parts o r injury correlated with behavioural deficits. Using standard behavioural tests adapted for use with mice, the mouse staircase test was shown to correlate with FMC infarct location and depth. The mouse cylinder test of fore limb asymmetry did not correlate with FMC infarct location and depth; despite this, a new analysis termed paw-dragging did correlate with FMC infarct location and depth. The results demonstrated that the FMC is functionally subdivided such that staircase deficits correlated with damage to the anterior FMC as opposed to the posterior FMC. As well, a small cortical infarct produced by ET- l induced PC prolife ration and migration. At 14 days post-injection, there were significantly more neuroblasts in the subventricular zone (SVZ) and the corpus callosum ipsilateral to injury. As NPCs proliferate and migrate toward ET-1-induced cortical infarcts, there is potential for therapeutic intervention to improve regeneration of lost tissue. This study provides a foundation for manipulating NPCs and analyzing their integration into the peri-infarct cortex.

Item Type: Thesis (Masters)
URI: http://research.library.mun.ca/id/eprint/11354
Item ID: 11354
Additional Information: Includes bibliographical references (leaves 93-104).
Department(s): Medicine, Faculty of
Date: 2013
Date Type: Submission
Library of Congress Subject Heading: Cerebrovascular disease--Treatment--Animal models; Endothelins--Physiological effect; Motor cortex--Effect of drugs on.
Medical Subject Heading: ; Brain Ischemia--therapy; Endothelin-1--therapeutic use; Mice.

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