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Investigation Of Hypoxia And Mitochondrial Dysfunction In The Central Nervous System Resulting From Focal And Systemic Inflammation

Chisholm, KI; (2015) Investigation Of Hypoxia And Mitochondrial Dysfunction In The Central Nervous System Resulting From Focal And Systemic Inflammation. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Inflammation is an important feature of several seemingly disparate neurological disorders, including multiple sclerosis, Parkinson’s disease and sepsis-related brain dysfunction. Inadequate oxygenation and mitochondrial dysfunction have been implicated in these and other CNS pathologies in which inflammation is found. Indeed, inflammation can have direct or indirect effects on mitochondrial function, for example, via reactive oxygen/nitrogen species, or through compromised perfusion respectively. However, the study of oxygenation and mitochondrial function in the CNS has been limited as tissues are typically excised for study in vitro, invariably exposing cells and their mitochondria to non-physiological environments. To overcome these limitations, the work described in this thesis involved the study of mitochondrial dysfunction and tissue oxygenation in the CNS during local and systemic inflammation in whole-animal preparations under physiological and pathophysiological conditions. The experiments include development of in vivo optical imaging techniques to assess the redox potential of mitochondria, without the application of dyes, and with an intact blood supply. Using this technique in conjunction with established methods we investigated mitochondrial function and tissue oxygen concentrations in cortical and retinal models of local and systemic inflammation. Our findings reveal that mitochondrial flavoprotein autofluorescence imaged in the cortex of anaesthetised mice can be used to assess an aspect of mitochondrial function (redox potential) in the CNS in vivo. Additionally, we show that certain types of inflammation are associated with tissue hypoxia in the brain and retina, and that this can have profound functional consequences for cerebral mitochondria during systemic inflammation. Hypothermia was also explored as a potential therapeutic strategy to attenuate inflammation-induced functional deficits. Collectively, these findings further our understanding of the mechanisms underlying neurological deficits associated with inflammation, and reveal mitochondrial redox state imbalances in certain inflammatory conditions with potential implications for the treatment of CNS disorders in which inflammation plays a role.

Type: Thesis (Doctoral)
Title: Investigation Of Hypoxia And Mitochondrial Dysfunction In The Central Nervous System Resulting From Focal And Systemic Inflammation
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Mitochondria, Flavoproteins, Sepsis, Oxygen, In vivo, Imaging, Microscope, Confocal, Retina, Cerebral cortex, Brain, Retina, Multiple Sclerosis, Age-related macular degeneration, Vasculature, Pial vessels
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: https://discovery.ucl.ac.uk/id/eprint/1470233
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