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dc.contributor.authorCairns, Elizabeth
dc.date.accessioned2020-01-21T19:06:15Z
dc.date.available2020-01-21T19:06:15Z
dc.identifier.urihttp://hdl.handle.net/10222/77295
dc.description.abstractGlaucoma is a blinding eye disease caused by death of retinal ganglion cells (RGCs). Intraocular pressure (IOP) is the only modifiable risk factor, and is the target of all current glaucoma therapeutics. However, IOP modification does not always successfully prevent further RGC loss. Therefore, therapies directly targeting RGC death may be additionally beneficial. The inflammatory cytokine tumor necrosis factor α (TNFα) is upregulated in glaucoma; however, how TNFα contributes to RGC death remains unclear. Recently, TNFα was suggested to promote calcium-permeable AMPA receptor (cpAMPAR) expression in experimental glaucoma, and was associated with excitotoxic RGC death. Furthermore, aside from IOP-lowering effects, cannabinoid receptor 1 (CB1) modulation is suggested to be neuroprotective in experimental glaucoma, likely through multiple mechanisms of action. In other neurons, CB1 modulation can inhibit TNFα-mediated increases in cpAMPAR expression; therefore, CB1-mediated neuroprotection in experimental glaucoma could include manipulation of this pathway. However, there are several disadvantages of direct CB1 orthosteric modulators, which may limit usefulness as clinically-relevant therapeutics. Recently, a new class of CB1 modulators have been developed, CB1 positive allosteric modulators (PAMs), which have the potential to modulate CB1, while limiting some disadvantages. Therefore, the aims of my thesis were to investigate TNFα-induced changes in cpAMPAR expression and modulation of this mechanism by CB1, and to investigate the ability of CB1 PAMs to decrease IOP and provide RGC neuroprotection in experimental glaucoma. IOP was assessed using rebound tonometry, and RGC density by Brn3a immunohistochemistry. Functional expression of cpAMPARs was evaluated through calcium imaging in ex vivo isolated retina. The data presented here demonstrate that: (1) TNFα incubation increases AMPA-induced changes in calcium dynamics, consistent with an increase in cpAMPARs observed in at least one model of experimental glaucoma; (2) CB1 PAMs can reduce IOP acutely; (3) chronic administration was not neuroprotective in two models of experimental glaucoma. Taken together, my work demonstrates that while TNFα-induced increases in cpAMPAR expression may contribute to RGC death, and CB1 modulation may be a therapeutic target in modifying this pathway, the CB1 PAMs explored here were insufficient in preventing RGC death when administered in experimental glaucoma.en_US
dc.language.isoenen_US
dc.subjectcpAMPARen_US
dc.subjectGlaucomaen_US
dc.subjectCannabinoiden_US
dc.subjectCB1en_US
dc.subjectIOPen_US
dc.subjectNeuroprotectionen_US
dc.subjectTNFαen_US
dc.titleStrategies for Neuroprotection and Intraocular Pressure Modulation in Experimental Models of Glaucomaen_US
dc.date.defence2017-12-06
dc.contributor.departmentDepartment of Pharmacology with Neuroscienceen_US
dc.contributor.degreeDoctor of Philosophyen_US
dc.contributor.external-examinerDr. Claire Mitchellen_US
dc.contributor.graduate-coordinatorDr. Ryan Pelisen_US
dc.contributor.thesis-readerDr. Kerry Goralskien_US
dc.contributor.thesis-readerDr. Ryan Pelisen_US
dc.contributor.thesis-supervisorDr. Melanie Kellyen_US
dc.contributor.thesis-supervisorDr. William Baldridgeen_US
dc.contributor.ethics-approvalReceiveden_US
dc.contributor.manuscriptsNot Applicableen_US
dc.contributor.copyright-releaseNot Applicableen_US
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