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

Abstract

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.

Conflict of interest statement

M.F. serves on the data, safety monitoring board for the ESCAPE-Next trial. He also serves as a consultant to Simcere USA and Lumosa of Taiwan. As an employee of the institution (UTHealth), S.I.S. has served in the following roles: as a site investigator in clinical trials sponsored by industry companies (Athersys, ReNeuron, San Bio, KM Pharma, Abbvie) for which UTHealth receives payments on the basis of clinical trial contracts; as an investigator on clinical trials supported by NIH grants, the Department of Defense, Let’s Cure CP, the TIRR Foundation, and the Cord Blood Registry Systems; as a principal investigator or co-investigator on NIH-funded grants in basic science and clinical research; and as principal investigator for an imaging analysis center for clinical trials sponsored by SanBio and ReNeuron. In his capacity as a UTHealth employee, Dr. Savitz has provided consulting services on behalf of UTHealth to ReNeuron, Lumosa, Deck Therapeutics, KM Pharma, Neurexcell, Abbvie, TMC Biodesign and ArunA. All compensation from such consulting arrangements have been paid to UTHealth.

© 2022. Springer Nature Limited.

Figures

Fig. 1. Elements of the ischaemic cascade in the neurovascular unit during acute ischaemic stroke.

Only selected elements are shown, and the signalling evolves over time after the onset of ischaemia. Oxygen and glucose deprivation leads to release of glutamate from astrocytes (1), which activates excitotoxic signalling within neurons, leading to neuronal injury and death, and activates microglia. Neuronal injury leads to the release of damage-associated molecular patterns (DAMPs), which also activate microglia (2), which consequently release pro-inflammatory cytokines that lead to further damage of neurons and promote endothelial activation and blood–brain barrier (BBB) opening. DAMPS also directly promote BBB breakdown. Leukocyte trafficking and migration to the ischaemic region (3) lead to further release of cytokines, amplification of neuroinflammation and continued neuronal damage. In parallel, neurons release ‘help me’ signals (4) that activate astrocytes and microglia to release factors that protect neurons. MMPs, matrix metalloproteinases; TH1 cell, T helper 1 cell; TH17 cell, T helper 17 cell.

Fig. 2. Outcomes of acute ischaemic stroke with and without cytoprotective therapy and reperfusion.

The aim of cytoprotective therapy administered as early as possible after stroke onset, is to ‘freeze’ the penumbra (left) so that the infarct core does not grow further before definitive reperfusion therapy can be completed. This protection minimizes the size of the final infarct (bottom left). Without cytoprotective therapy, the final infarct size could be larger despite successful reperfusion (bottom right). Cytoprotective therapy can only be beneficial if reperfusion is achieved before the protective effects diminish. If reperfusion therapy is not administered within this time, the final infarct could be as large as it would have been without cytoprotection (bottom centre). Reperfusion injury can lead to haemorrhagic transformation regardless of whether cytoprotective therapy is used.