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Type: Thesis
Title: Creatine neuroprotection in the retina
Author: Sia, Paul lkgan
Issue Date: 2018
School/Discipline: Adelaide Medical School : Ophthalmology and Visual Sciences
Abstract: Studies concerning retinal neurodegeneration have increased remarkably over recent decades as efforts have focused on elucidating mechanisms of damage and ways to halt the degenerative progression. The retina is a complex structure that consists of multiple layers of different types of neurons. The retinal ganglion cell (RGC) layer is particularly susceptible to damage and its degeneration is a feature of conditions such as glaucoma. In addition to well-described mechanisms of retinal neuron injury in glaucoma, such as mitochondrial dysfunction and oxidative stress, energetic failure has also been postulated. In this thesis, emphasis is directed towards investigating the retinal effects of creatine, which has been postulated to act by overcoming tissue bioenergetic failure, in culture and animal models of metabolic dysfunction. There are two papers to this thesis. The first paper characterizes various markers of RGC in a well-known model of retinal ganglion cell injury – N-methyl- D-aspartate (NMDA)-induced retinal excitotoxicity. As there exists no gold standard marker for RGC for the purposes of neuroprotection studies, we aimed to compare four recent ganglion cell markers by retinal whole-mount immunohistochemistry and observe how they changed over time following NMDA exposure. We found that NMDA-induced RGC injury was maximal within the first 24 hours of exposure and there is good consistency between markers Brn3a, RBPMS and γ-synuclein. Of all markers tested, Brn3a was the most useful marker of RGCs to employ in studies looking at loss and counteraction of loss for these cells. This finding was immediately employed for the in vivo work in the second study. The second paper addresses the effects of creatine in models of retinal injury both in vitro and in vivo. Firstly, a rat retinal culture model of energetic dysfunction using sodium azide was used. Levels of apoptosis, ATP and reactive oxygen species were also tested. Creatine was found to partially protect cultured rat retinal neurons from energetic failure, as well as reducing oxidative stress and apoptosis. The study then moved on to in vivo experiments whereby effects of oral creatine supplementation in rat models of NMDA-induced retinal excitotoxicity and retinal ischaemia were examined. RGC reductions were found to be up to 70% but these losses were not significantly reduced by creatine supplementation. When apoptotic levels were assessed, there remained no significant difference between the creatine-fed and control group of rats that underwent NMDA-induced retinal toxicity. Further studies, especially on the mechanisms of creatine neuroprotection, would need to be performed to explain the discrepancy in the ability of this compound to provide neuroprotection in vitro but not in vivo.
Advisor: Casson, Robert
Wood, John
Dissertation Note: Thesis (MPhil) -- University of Adelaide, Adelaide Medical School, 2018
Keywords: Creatine
retinal ganglion cells
retinal ischaemia
retinal excitotoxicity
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at:
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