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

• Published in: Nature reviews. Neurology Vol. 18; no. 4; pp. 193 - 202
• Main Authors: Fisher, Marc, Savitz, Sean I.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2022; Nature Publishing Group
• Subjects: 692/617; 692/617/375/1370; Brain; Brain Ischemia - drug therapy; Cytoprotection; Drug development; Endovascular Procedures; Humans; Ischemia; Ischemic Stroke; Medicine; Medicine & Public Health; Neurology; Reperfusion; Review; Review Article; Stroke; Stroke - drug therapy; Thrombectomy; Treatment Outcome
• ISSN: 1759-4758; 1759-4766
• DOI: 10.1038/s41582-021-00605-6

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. Key points Highly successful reperfusion therapy with intravenous thrombolysis and endovascular thrombectomy is now widely available for the treatment of acute ischaemic stroke, making cytoprotective therapy a viable additional treatment approach. Previous attempts to develop cytoprotective therapy have been unsuccessful, but this approach should now be reconsidered as an adjunctive therapy to thrombolysis and thrombectomy. New cytoprotective drugs should be developed to target multiple aspects of the ischaemic cascade, and previously developed drugs should be reconsidered. Trials should be conducted to evaluate the effects of cytoprotective drugs when administered before or after reperfusion therapy or both. Advanced brain imaging should be used to select patients who are most likely to benefit from cytoprotective treatment for enrolment in new trials.