Pharmacological brain cytoprotection in acute ischaemic stroke - renewed hope in the reperfusion era

For over 40 years, attempts to develop treatments that protect neurons and other brain cells against the cellular and biochemical consequences of cerebral ischaemia in acute ischaemic stroke (AIS) have been unsuccessful. However, the advent of intravenous thrombolysis and endovascular thrombectomy has taken us into a new era of treatment for AIS in which highly effective reperfusion therapy is widely available. In this context, cytoprotective treatments should be revisited as adjunctive treatment to reperfusion therapy. Renewed efforts should focus on developing new drugs that target multiple aspects of the ischaemic cascade, and previously developed drugs should be reconsidered if they produced robust cytoprotective effects in preclinical models and their safety profiles were reasonable in previous clinical trials. Several development pathways for cytoprotection as an adjunct to reperfusion can be envisioned. In this Review, we outline the targets for cytoprotective therapy and discuss considerations for future drug development, highlighting the recent ESCAPE-NA1 trial of nerinetide, which produced the most promising results to date. We review new types of clinical trial to evaluate whether cytoprotective drugs can slow infarct growth prior to reperfusion and/or ameliorate the consequences of reperfusion, such as haemorrhagic transformation. We also highlight how advanced brain imaging can help to identify patients with salvageable ischaemic tissue who are likely to benefit from cytoprotective therapy. In this Review, Fisher and Savitz consider how the era of reperfusion therapy in ischaemic stroke provides new hope for the development of cytoprotective therapies to further improve outcomes, highlighting how promising recent findings can be built on to benefit patients.

Automated summary

This review discusses the history of ischemic stroke treatment and the role of cytoprotective therapy in reperfusion treatment. The article suggests revisiting cytoprotective treatments and outlines strategies for developing new drugs and reevaluating previous ones. Additionally, the review introduces novel approaches to clinical trials and the application of advanced brain imaging techniques in cytoprotective therapy.