Using zebrafish for pre-clinical brain haemorrhage research

Stroke is a leading cause of death and disability. Intracerebral haemorrhage accounts for 10-15% of strokes and has the worst outcomes, with a one month case-fatality of 40% and disability in most survivors. Apart from acute and chronic blood pressure lowering, there are 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 many novel therapies showing benefit in ischaemic stroke models, none have translated to an effective clinical treatment. Continuing to use this approach for intracerebral haemorrhage research may be ethically flawed. Nevertheless, there remains a great need for new treatments and it is essential to continue to interrogate disease pathophysiology in stroke using alternative models.

The use of zebrafish (Danio rerio) is becoming an increasingly favoured approach to investigate disease pathogenesis. Perhaps the most important characteristic of the zebrafish model is the transparency of embryonic development, allowing for the visualisation of internal organogenesis. Importantly, in the UK, zebrafish larvae up to the age of five days post-fertilisation are not classified as a protected species under the UK Animals (Scientific Procedures) Act 1986. 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.

• First person article in Disease Models and Mechanisms
• Dementia Researcher blog post: A resource for translational stroke research