ETHERISCH

Ischemic stroke is a major cause of death and morbidity worldwide and therefore an important public health issue. Current treatment, limited to removal of the large vessel occlusion at origin of ischemia, is offered to a minority of patients and not always effective. Novel adjunct therapies are therefore needed. There is potential promise in therapeutic approaches aimed to optimize microvascular function in the affected brain regions so as to limit the expansion of the core of the ischemic infarct before recanalization and to reduce the risk of malignant edema and hemorrhagic transformation. Pharmacological approaches to this end include the stimulation of endogenous endothelial protective pathways and the prevention of inflammation-induced thrombosis, also known as thromboinflammation. This proposal aims to explore the benefit of endothelial cell stimulation with sphingosine-1 phosphate receptor-1 (S1P1) agonists either alone or in conjunction with inhibition of thromboinflammation in mouse models of ischemic stroke. We hypothesize that these approaches can be safely combined to optimize tissue perfusion and possibly preserve blood-brain barrier function in the ischemic cortex, thus mitigating the impact of large artery occlusion and improving the efficacy of standard therapy. In order to better appreciate the potential benefit of targeting these pathways we will first use genetic, pharmacological, molecular and imaging tools to explore their spatial and temporal engagement, mechanism of action, and inter-play in the ischemic cerebral cortex. We will then attempt combinatorial therapy in mouse models of ischemic stroke and address if S1P1 stimulation either alone or in combination with inhibitors of thromboinflammation can offer benefit in the context of endothelial dysfunction triggered by hyperglycemia in diabetes mellitus, a major risk factor for and disease modifier of ischemic stroke. We expect that this project will inform on the potential benefits of pharmacological stimulation of microvascular perfusion for ischemic stroke and assist the design of future clinical trials in this domain.