Reconsidering Neuroprotection in the Reperfusion Era

Neuroprotection to prevent infarct progression as a potential treatment for acute ischemic stroke carries a long and disappointing history. The failures of these prior neuroprotection trials have many potential explanations that encompass both problems with the preclinical assessment of these drugs and the design/implementation of clinical trials.1 Prior development of neuroprotection has focused primarily on its use as a monotherapy, and no clinical trial was designed to determine whether neuroprotection could extend the time window for successful reperfusion or ameliorate the consequences of reperfusion. Acute stroke therapy has now entered the era of highly effective reperfusion with the recent publication of 5 positive thrombectomy trials.2 Combining neuroprotection with intravenous or intra-arterial reperfusion therapy is now an important next step in the development of acute stroke therapies. One approach to neuroprotection would be to initiate therapy early after ischemic stroke onset, either in the ambulance or at a primary stroke center/community hospital to potentially extend the time window for intravenous or intra-arterial therapy. A second approach would be to use neuroprotection during or after partial or complete reperfusion to reduce the consequences of reperfusion injury. Both future neuroprotective approaches will require preclinical studies that anticipate novel clinical trial designs and trials that will be organized and evaluated differently than past monotherapy neuroprotection trials. Acute ischemic stroke therapy is designed to reduce infarction of hypoperfused brain tissue and limit the expansion of already irreversibly injured tissue when treatment is initiated, leading to smaller infarction and improved clinical outcomes.3,4 Severely hypoperfused but still potentially viable ischemic brain represents the ischemic penumbra, whereas irreversibly injured tissue is the ischemic core.5 Early after stroke onset, most patients with a large vessel occlusion (LVO) have an extensive ischemic penumbra that can be salvaged by timely reperfusion. This concept was proven …