The Roles of TRP Channels in Ischemic and Cold Spreading Depolarization
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Authors
Hancock, Dominique
Date
Type
thesis
Language
eng
Keyword
Stroke , Spreading depolarization , Ischemia
Alternative Title
Abstract
Spreading depolarization (SD) is a propagating wave of cellular depolarization that traverses through the higher cerebral grey matter, leading to neuronal swelling and injury. SD is caused by the failure of the sodium-potassium activated adenosine triphosphatase (Na+/K+ ATPase) pump. SD occurs in cases such as ischemic stroke where it is shown to expand the region of tissue damage. While it is known that SD is responsible for worsening neurological outcomes after stroke, there are still a lack of pharmaceutical targets. This study focuses on transient receptor potential vanilloid 4 (TRPV4) and transient receptor potential melastatin 8 (TRPM8) to investigate their contribution to SD onset and subsequent damage.
TRPV4 inhibition by the selective antagonist, HC-067047, in a brain slice model of ischemic stroke (oxygen and glucose deprivation, OGD) delayed SD onset and slowed SD propagation speed in one mouse strain (C57BL/6) but not the other (CD1(ICR)). There was, however, a reduction in OGD-mediated swelling, measured by a change in light transmittance (ΔLT), with pre-treatment of the TRPV4 antagonist in both mouse strains. In C57 mice, at 10uM HC-067047, there was a 26% reduction in ΔLT from control. In CD1 mice 10uM HC-067047 elicited a 25% reduction in ΔLT from control, 1uM HC-067047 a 42% reduction in ΔLT, and 0.3uM HC-067047 a 51% reduction in ΔLT. As well, TRPV4 agonism by GSK1016790A (10uM) delayed SD onset in CD1 mice. Together, this suggests that the TRPV4 channel has a multifaceted role in SD and cell swelling in the ischemic brain.
TRPM8 was investigated for its contribution to the generation of cold temperature induced spreading depolarization (cold-SD); however, its specific antagonist PBMC (25nM) did not affect cold-SD initiation, propagation, or subsequent swelling. In our other experiments regarding cold-SD properties, we demonstrated a positive shift in extracellular potential by +2mV mediated by tissue cooling. As well, we showed that cold-SD is a true depolarization event marked by a negative shift in extracellular potential of -2-4mV coinciding with the imaged cold-SD wavefront. We conclude that cold-SD is evoked by dysfunction of the Na+/K+ ATPase pump caused by the reduction in metabolic rate at near-freezing temperatures.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.