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THROMBOLYTICS TO AID CLOT LYSIS IN INTRACEREBRAL HAEMORRHAGE: IDENTIFYING STRATEGIES TO MAXIMISE BENEFIT
[Thesis]. Manchester, UK: The University of Manchester; 2017.
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Abstract
Intracerebral haemorrhage (ICH) is a subtype of stroke caused by bleeding into the brain. ICH has a high case fatality rate of 42% at 1 month and only 20% of survivors regain independence. Large clinical trials are currently underway to assess the potential benefit of minimally invasive surgery (MIS) in combination with the thrombolytic alteplase in ICH. Although preliminary results are promising alteplase is known to be neurotoxic and may therefore exacerbate damage when administered in ICH, reducing its overall effectiveness. Alternative thrombolytics to alteplase do exist and the initial aim of this project is to establish the toxicity of these compounds in comparison with alteplase in cell culture. Here the optimisation of a cell culture model of neuronal injury is described. This utilizes a glial-neuronal rat cortical co-culture with 5μM of FUDR added during seeding. After 12 days of culture cells are treated with the pro-inflammatory cytokine interleukin-1β as a full media change with serum free medium. LDH release is used to measure viability after 72h and this resulted in a low basal cell death which is increased moderately with 0.1ng/mL of IL-1β. The activity of each thrombolytic has also been determined using a clotting assay. These can now be combined to compare toxicity in culture. Optimising the original MIS approach represents a ‘back-translation’ of what has been shown to be effective in the clinic and how this can be improved further using basic research. All drugs used are already licenced for use in patients and as such, the use of an alternative thrombolytic could be implemented relatively easily to improve mortality and functional outcomes after ICH.