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Title: Neuroprotection by noble gases and other drugs in models of trauma
Author: Malhotra, Diya
ISNI:       0000 0004 9350 0695
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Traumatic Brain Injury (TBI) is a debilitating and complex condition that consists of a ‘primary’ injury followed by a ‘secondary’ injury, which develops over time. Much of the morbidity occurs due to the secondary injury, for which there are currently no approved pharmacotherapies. This thesis is structured as a study of models of TBI and an investigation of drugs to treat the condition. First, an injury quantification methodology was developed in an in vitro model of TBI using organotypic hippocampal slice cultures and propidium iodide fluorescence. Second, ‘combination therapies’ with the noble gases xenon and argon, progesterone and meloxicam to modulate multiple secondary injury mechanisms were explored. 25% argon and 3μM, 10μM and 25μM progesterone are additively protective at 72 hours. Co-administering 25μM progesterone with 25% argon (29±6% protective) abolished injury. Co-administering 50% argon (41±5% protective) synergistically abolished injury with 3μM progesterone and additively abolished injury with 10μM and 25μM progesterone. 25% xenon and 3μM, 10μM and 25μM progesterone were additively protective at 72 hours. Co-administering 25μM progesterone with 25% xenon (44±5% protective) abolished injury. 25% argon in combination with 0.1μM and 1μM meloxicam works additively. Neuroprotection by 25% argon doubled when co-administered with 1μM meloxicam. 25% xenon and 1μM meloxicam are additive, abolishing injury at 72 hours unlike sub-maximally effective 25% xenon. Third, experiments to calibrate a controlled cortical impact (CCI) model of in vivo TBI were conducted. Contusion volume was measured and the expression of inflammatory cytokines was quantified in blood and brain samples at different time points. Finally, a Drosophila melanogaster model of polytrauma was developed as a high throughput assay. Drosophila are more sensitive to trauma in the early phase of their circadian day. Hypothermia treatment (40C) increased survival to the level of uninjured shams at 24 hours and more than doubled survival over 14 days.
Supervisor: Dickinson, Robert Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral