A New Paradigm in Protecting Ischemic Brain: Preserving the Neurovascular Unit Before Reperfusion

Abstract

Of the ~795,000 strokes that occur each year in the USA, ~695,000 are ischemic strokes (IS) where a clot occludes a major cerebral artery. About half of these IS patients present with so-called penumbra, defined as a hypoperfused tissue immediately surrounding the ischemic core that is severely deprived of oxygen and at risk for deterioration. Collateral vessels can provide sufficient oxygen and nutrients to temporarily maintain neuronal structure in the penumbra but not enough to support function. Thus, the at-risk tissue has the potential for functional recovery if blood flow is restored, but will irreversibly infarct if recanalization is not achieved, resulting in neurological deterioration. Additionally, though collateral circulation can transiently maintain penumbra viability, injury mechanisms such as excitotoxicity and ATP depletion will have already been initiated. Thus, it is imperative to administer therapies that can alleviate ischemia-induced cell death, restore energy metabolism, and halt pathogenic cascades as soon as possible after occlusion in order to protect the at-risk tissue until reperfusion therapies can be employed. Excitingly, the recent breakthroughs in acute IS reperfusion therapy have opened new opportunities for such adjunct neuroprotective treatments. This chapter provides a description of the penumbra tissue, followed by a brief overview of the emerging standard of care for acute IS based on the recent positive clinical trials using IV tPA and mechanical thrombectomy devices. We will then describe the promising use of adjunctive therapies to enhance the benefits of recanalization therapies. In particular, we will discuss the concept of oxygen therapy and oxygen carriers as a valid approach for “combination therapy” to protect the penumbra until reperfusion. Finally, we will discuss the future challenges of clinical trials in acute IS patients and highlight the need for new trial designs to test the potential benefit of combination therapies.