Vascular Dysfunction in Brain Hemorrhage: Translational Pathways to Developing New Treatments from Old Targets

Hemorrhagic stroke which is a form of stroke that affects 20% of all stroke patients is a devastating condition for which new treatments must be developed. Current treatment methods are quite insufficient to reduce long term morbidity and high mortality rate, up to 50%, associated with bleeding into critical brain structures, into ventricular spaces and within the subarachnoid space. During the last 10-15 years, significant advances in the understanding of important mechanisms that contribute to cell death and clinical deficits have been made. The most important observations revolve around a key set of basic mechanisms that are altered in brain bleeding models, including activation of membrane metalloproteinases, oxidative stress and both inflammatory and coagulation pathways. Moreover, it is now becoming apparent that brain hemorrhage can activate the ischemic stroke cascade in neurons, glial cells and the vascular compartment. The activation of multiple pathways allows comes the opportunity to intervene pharmacologically using monotherapy or combination therapy. Ultimately, combination therapy or pleiotropic compounds with multi-target activities should prove to be more efficacious than any single therapy alone. This article provides a comprehensive look at possible targets for small molecule intervention as well as some new approaches that result in metabolic down-regulation or inhibition of multiple pathways simultaneously.