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Title: The role of hypoxia in neuroinflammatory disease
Author: Desai, R. A.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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Multiple sclerosis (MS) is an inflammatory demyelinating and degenerating disease of the central nervous system (CNS) that typically starts with a relapsing-remitting course of neurological deficits. Among the enigmas in the disease are 1) the cause of the neurological deficits, 2) the cause of the demyelination, 3) the cause of the degeneration, and 4) the cause of the disease itself. This thesis examines the novel hypothesis that tissue hypoxia might illuminate at least some of these enigmas. Tissue hypoxia can easily account for loss of function in a tissue as heavily dependent on oxidative phosphorylation as the CNS, and it can similarly selectively kill cells such as oligodendrocytes and neurons/axons if they are reliant on oxidative metabolism. Hypoxia can also promote inflammation in tissues and thereby reduce the threshold for the initiation of inflammatory disease. Three experimental models have been examined, namely experimental autoimmune encephalomyelilits (EAE, a common model of MS), an experimental model of the demyelinating Pattern III MS lesion, and animals rendered temporarily hypoxic due to placement in an atmosphere of 10% oxygen. We provide chemical, physical and therapeutic evidence that tissue hypoxia is, in part, responsible for 1) neurological dysfunction in EAE, 2) the demyelination in the model Pattern III lesion, in association with nitric oxide and superoxide, 3) by extension, perhaps neurodegeneration, and 4) a sensitization of the CNS to pro-inflammatory conditions, including evidence of the special sensitivity of oligodendrocytes to hypoxia. We conclude that true tissue hypoxia is a hitherto-unrecognised, but potentially important, factor in several of the cardinal characteristics of MS.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available