Our understanding of the disease mechanisms underlying intracerebral haemorrhage (ICH) is incomplete and as such, our ability to prevent ICH or improve outcomes once bleeding has occurred is limited. It is essential, therefore, that we continue to interrogate ICH pathophysiology using new pre-clinical approaches. The aim of this work was to investigate the use of zebrafish as an alternative model system for studying the causes and pathological consequences of ICH. 

Zebrafish larvae are transparent, allowing for easy visualisation of brain tissue in intact animals. Spontaneous brain haemorrhage was induced using genetic and chemical manipulation. Live imaging of larvae derived from transgenic zebrafish reporter lines (expressing fluorescent proteins in a range of cell types) was performed to record cellular responses in the brain immediately after ICH. Locomotor function following ICH was also analysed.

We show that spontaneous brain haemorrhage in zebrafish larvae is associated with 1) significant cell death within the brain, 2) increased activation of macrophages within brain injury sites, 3) a significant reduction in locomotor function and 4) increased expression of the inflammatory cytokine interleukin-1β (il-1β). Furthermore, we show that inhibition of il-1β is protective against brain cell death in this model.

Zebrafish larvae are a powerful system for studying ICH biology in real-time, allowing for observations which are not possible using rodents. These data indicate that the pathological consequences of brain bleeding are conserved between zebrafish and humans, thereby validating the use of this model as an important new tool for studying ICH pre-clinically.

USING ZEBRAFISH TO MODEL HAEMORRHAGIC STROKE