Large Mammals - translational stroke models in sheep

International academic and industrial expert consortia (STAIR, STEPS) suggest stringent preclinical research strategies for stroke including validation of novel treatment strategies in gyrencephalic animal models. However, many existing gyrencephalic animal models are expensive, constrained by ethical considerations or limited by species-specific anatomical restrictions. Importantly, many large animal models do not allow long term investigations, being crucial for robust safety and efficacy assessments. To overcome these limitations, an ovine model of cerebral ischemia by permanent middle cerebral artery occlusion (MCAO) in sheep was established. After detailed characterization of the model itself, it was utilized in acute stroke treatment studies, for example using nitrogen monoxide, but also in long term experiments such as assessment of autologous bone marrow cell therapy. Additionally, frameless stereotaxic methods were established that enable local administration of cells and/or substances for different purposes. Moreover, the ovine model is routinely used for state-of-the-art imaging studies (MRI, PET and combined PET/MRI) including automatic image processing and analysis using ovine stereotaxic atlas. Major strengths of the ovine MCAO model comprise reproducible lesion size, capability for long term studies and suitability for clinical imaging procedures, as well as relatively low costs. The transcranial approach avoids enucleation, enabling testing of neurological functions without modelling effects, but at the cost of artificial intracranial pressure profiles. The model has also been adopted for transient MCAO. Keywords: sheep, MCAO, ischemia, translational studies, Nitric Oxide, Bone Marrow, brain atlas