Grant: Team Grant: Cerebrovascular Diseases

There are presently no neuroprotective drugs with efficacy to improve outcomes after lacunar stroke. Fundamental challenges to advancing treatment of lacunar stroke are its heterogeneity in terms of cause, pathology, and the lack of mechanistic endpoints in clinical studies. Mechanistic endpoints, necessary for appropriate targeting of treatment, have been lacking due to our limited ability to validate and monitor relevant pathologic processes in clinical populations. Nonetheless, understanding the mechanisms contributing to neuronal and vascular disruption and developing mechanistic endpoints on the basis of this understanding holds great promise to unravel the heterogeneity of lacunar stroke, assign treatments appropriately, and detect significant treatment effects when they exist. Spreading depolarizations are a pathology of cerebral gray matter that originate spontaneously in injury foci where they seem to facilitate or even mediate irreversible cellular damage. Whether or not they are deleterious to the tissue seems to be intimately linked to the composition of the brain extracellular microenvironment and to the level of brain perfusion and in consequence brain energy supply. Waves of spreading depolarization propagate away from an injury focus. The spreading depolarization waves can be detected electrophysiologically in these uninjured regions where they appear to be relatively harmless In contrast to the deleterious effects in injured areas. These remarkable features suggest that spreading depolarizations could be used as a mechanistic endpoint in clinical studies of SVD to detect lesion progression. Nevertheless, the first step and the purpose of the present grant proposal is to firmly define their role in lesion progression in a relevant animal model for SVD.