Using zebrafish for pre-clinical brain haemorrhage research

Stroke is a major cause of death and complex disability. Intracerebral haemorrhage accounts for 10-15% of strokes and has the worst outcomes, with a 1-month case-fatality of 40% and disability in most survivors. Unlike ischaemic stroke, the incidence of intracerebral haemorrhage has not fallen, due to an aging population and increasing use of antithrombotic drugs to prevent vaso-occlusive events. Apart from acute and chronic blood pressure lowering, we have no treatments to prevent intracerebral haemorrhage or improve outcomes once haemorrhage occurs.

Rodent models of stroke have been critical in providing insights into stroke pathophysiology. However, despite over a thousand novel therapies showing benefit in ischaemic stroke models, none have translated to an effective clinical treatment, with large numbers of protected animals required for such experiments. There remains therefore a great need for new treatments and it is essential to continue to interrogate disease pathophysiology in stroke using alternative models to develop new treatment strategies.

The use of zebrafish (Danio rerio) is becoming an increasingly favoured approach to investigate disease pathogenesis, offering a number of advantages over other commonly used model species, including rapid reproduction rates and external embryogenesis. Perhaps the most important characteristic of the zebrafish model is the transparency of embryonic development, allowing for the visualisation of internal organogenesis. Taking advanatage of this we have generated novel genetic and chemically-induced zebrafish embryo / larvae models of stroke. In addition to brain haemorrhage, these models exhibit increased transcription of several innate immune genes, including interleukin-1 (IL-1) and interferon signature genes.

This project aims to further investigate how the innate immune system and cerebrovasculature interact in the context of experimental brain haemorrhage in zebrafish. Our long term vision is to establish the use of zebrafish embryos / larvae as a model of brain haemorrhage, providing an ethically more acceptable, rapid throughput system for pre-clinical drug development in the future.