Amatruda, M; (2017) Exploring the role of hypoxia in neuroinflammatory disease and the use of oxygen as a therapy. Doctoral thesis , UCL (University College London).

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Abstract

Multiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system (CNS). Pathological studies have revealed that MS lesions can have hypoxia- like properties, raising the possibility that the inflamed CNS may suffer an energy deficit. We recently demonstrated that the spinal cord of rats with active experimental autoimmune encephalomyelitis (EAE, a model of MS) is hypoxic, and that hypoxia can be reversed by inspiring oxygen-enriched air. This thesis examines the contribution of hypoxia to the neurological deficits, and the use of oxygen as a therapy. Demyelinating and non-demyelinating models of EAE in rats were evaluated, namely active and passive EAE respectively. Room air controls were used for comparison. Assessment of neurological deficits in active EAE revealed that oxygen (95%) promptly improved neurological function in paralysed rats, within only 1 hour of exposure. Furthermore, prolonged administration of oxygen (75%) applied either prophylactically (from the day of immunisation for 23 days) or therapeutically from the onset of disease (for 24, 48 or 72 hours) produced a greater and long-lasting amelioration of disease severity. Interestingly, oxygen treatment from disease onset reduced oligodendrocyte cell-stress and death, demyelination, microglial activation and macrophage infiltration in the spinal cord, without exacerbating oxidative damage. The protective effect was proportional to the duration of the treatment and significant in rats treated for 72 hours. Other experiments have revealed that the spinal cord of rats with passive EAE is also hypoxic and oxygen treatment significantly ameliorated disease progression when administered prophylactically. We also tested polynitroxylated pegylated hemoglobin (PNPH) as an alternative oxygen-based treatment in active EAE, revealing an acute improvement of the neurological function 1 hour after the injection of PNPH. We conclude that hypoxia contributes to neurological deficits and demyelination in inflammatory autoimmune demyelinating disease, and that oxygen therapy can reduce both the deficits and the demyelination.

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