Zebrafish drug screening identifies candidate therapies for neuroprotection after spontaneous intracerebral haemorrhage

Despite the global health burden, the treatment of spontaneous intracerebral haemorrhage (ICH) is largely supportive and translation of specific medical therapies has thus far been unsuccessful. Zebrafish larvae offer a unique platform for drug screening to rapidly identify neuroprotective compounds following ICH. We applied the Spectrum Library compounds to zebrafish larvae acutely after ICH to screen for decreased brain cell death and identified 150 successful drugs. Candidates were then evaluated for possible indications with other cardiovascular diseases. Six compounds were identified including two angiotensin converting enzyme inhibitors (ACE-I). Ramipril and quinapril were further assessed to confirm a significant 55% reduction in brain cell death. Proteomic analysis revealed potential mechanisms of neuroprotection. To validate translation, sub-analysis of the INTERACT2 clinical trial dataset was performed to assess effects of ACE-I when administered to patients acutely. This revealed a significant association (P=0.009) between ACE-I use after ICH and a good outcome (mRS 0-2) at 90 days. The zebrafish larval model of spontaneous ICH can be used as a reliable drug screening platform, and has identified therapeutics which may offer neuroprotection following acute ICH.