Better understanding the pathophysiology of ischemic stroke using in vivo imaging approaches in awake animals: how to improve translation to clinic – THRONE

Therapeutic approaches aim to restore cerebral blood flow (CBF) with the endovascular thrombectomy enlarging the narrow therapeutic window of fibrinolysis from 4.5 hours to up to 6-24 hours, opening avenues for the development of new strategies to protect or repair the brain. However, in the last decades, while many experimental therapies have been identified in animal stroke models (targeting thrombolysis, neuronal death or inflammation), all have failed when translated to the clinic. This “translational roadblock” is commonly attributed to inherent weaknesses of preclinical studies that include a lack of clinical relevance. The use of preclinical stroke models under anesthesia (targeting NMDA and GABA receptors, influencing heart rate and cerebral blood flow) may explain this failure. Accordingly, the aims of our proposal are 1/to develop a set of innovative in vivo functional and molecular imaging tools (ultrasound and MRI) to visualize stroke-related events in the awake living brain; 2/ to investigate the spatiotemporal evolution of the functional and molecular events occurring following ischemic stroke in awake animals (from onset to later phases) and 3/ to assess the efficacy of therapeutic candidates in models of stroke closed as possible with the clinical situations. This project will also allow us to propose an innovative platform to test future therapeutics of ischemic stroke with a better chance of translation to human.