We identified references for this Personal View by searching PubMed for articles published between Jan 1, 2010, and Oct 1, 2015. The search terms used were “ischemic stroke”, “neuroprotection”, “therapy”, “clinical trials”, and “preclinical studies”. Articles were restricted to those published in English. Additional papers were identified by searching the authors' personal files. We also searched all major registries of clinical trials including ClinicalTrials.gov, Stroke Trials Registry,
Personal ViewNeuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation
Introduction
By 2050, more than 1·5 billion people in the world will be aged 65 years or older, and the global burden of stroke will keep increasing in parallel with the ageing population.1 Stroke represents the second single most frequent cause of death for people older than 60 years, the most frequent cause of permanent disability, and the second most common cause of dementia, and uses approximately 3–7% of the total health-care expenditure in high-income countries. Consequently, there is a pressing need to investigate new treatments for patients with acute ischaemic stroke, which constitutes most strokes.
The main aim of acute stroke treatment is to salvage the ischaemic penumbra or volume of hypoperfused, non-functional, yet still viable tissue surrounding the infarcted core. Indeed, remarkable progress has been made in the management of patients with acute ischaemic stroke during the past 10 years, with the widespread implementation of specialist stroke units, evidence of the efficacy of intravenous thrombolytic treatment, and reporting of randomised controlled trials (RCTs) establishing the value of endovascular thrombectomy. Several key players in ischaemic cell death within the penumbra have been identified, including excitotoxicity, oxidative and nitrosative stress, and inflammation;2 however, numerous clinical trials have failed to show efficacy of drugs that modulate one or more of these mechanisms in patients with acute ischaemic stroke, despite promising preclinical data.3
Although the traditional scientific definition of neuroprotection refers to minimising the harmful effect of ischaemia at the level of the neuron, from the pragmatic point of view of patients and physicians, neuroprotection means keeping neuronal and glial damage under the threshold of symptom manifestation,4 and this definition will be the concept applied in this Personal View. The discovery of the role of glutamate and calcium ions in neuronal cell death after hypoxia and ischaemia (known as excitotoxicity) in the late 1980s transformed the entire field of stroke research.5 Throughout the following two decades, which also saw the publication of the seminal National Institute of Neurological Disorders study establishing the value of alteplase induced reperfusion,6, 7 stroke researchers worldwide eagerly anticipated a new era in which reperfusion and neuroprotection would revolutionise the treatment of acute ischaemic stroke. Since then, experimental studies, mostly in rodent models of stroke, have overwhelmingly suggested that the brain could be acutely protected from focal ischaemia with a plethora of different therapeutic strategies. These interventions ranged from pharmacologically blocking neurotransmitter receptors to intercepting cell death pathways, as well as the induction of hypothermia or hyperoxygenation.8 However, several hundred phase 2 studies and dozens of phase 3 RCTs failed to show efficacy of any of these promising strategies.9 Numerous articles and symposia have tried to explain these failures, principally questioning the value of modelling stroke in rodents, or criticising the design of clinical neuroprotection trials.10, 11, 12
This Personal View aims to summarise the main reasons underpinning the failed translation of neuroprotection from bench to bedside in acute ischaemic stroke, and to provide an update on the status of major ongoing and recently completed RCTs assessing different neuroprotective strategies in patients with acute ischaemic stroke. Given the broad scope of the topic, this paper focuses mainly on those approaches geared to modulate excitotoxicity, oxidative and nitrosative stress, and inflammation.
Section snippets
Limitations of current therapies
A meta-analysis of individual patient data from nine randomised trials comparing intravenous alteplase with placebo or open control showed alteplase increased the odds of a good stroke outcome (ie, a modified Rankin scale score of zero or one at 3–6 months), with earlier treatment associated with bigger proportional benefit.13 However, intravenous alteplase has a low successful recanalisation rate, which reduces the overall efficacy of this approach.14 The efficacy and safety of intra-arterial
Excitotoxicity
Excitotoxicity was the first molecular mechanism of ischaemic brain tissue damage to be identified and intensively studied.5 Excitotoxicity refers to the rapid and massive release and inhibited reuptake of the excitatory aminoacid glutamate as a result of energy failure. The accumulation of glutamate overactivates a plethora of downstream signalling pathways, many of which involve a surge in calcium influx, causing the intracellular calcium concentration to increase. The prevention of
Failed translation of neuroprotection and future directions
The clinical evidence discussed in this Personal View highlights the fundamental role of restoring normal brain perfusion after the onset of stroke to obtain effective neuroprotection. Endovascular thrombectomy, either alone or preceded by systemic thrombolysis, is the most effective treatment currently available to achieve this goal. However, endovascular thrombectomy can be administered to only a minority of patients and the treatment can be futile (or harmful) if it does not reperfuse
Conclusions
The accumulation of failed results in the clinical translation of a neuroprotective treatment for patients with acute ischaemic stroke indicates that the implementation of new strategies is needed both in the preclinical field and in the clinic. Therefore, we argue that before funding and initiation of a clinical trial of a neuroprotective drug, the candidate drug should have a clearly defined molecular mechanism of action, a molecular target, an established toxicity profile, and appropriate
Search strategy and selection criteria
References (113)
- et al.
Gaps between aims and achievements in therapeutic modification of neuronal damage (“neuroprotection”)
Neurotherapeutics
(2015) - et al.
The science of stroke: mechanisms in search of treatments
Neuron
(2010) Neuroprotection for ischemic stroke: past, present and future
Neuropharmacology
(2008)- et al.
Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischemic stroke: a meta-analysis of individual patient data from randomized trials
Lancet
(2014) - et al.
MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study
Lancet Neurol
(2012) - et al.
Neuronal oxidative stress in acute ischemic stroke: sources and contribution to cell injury
Neurochem Int
(2013) - et al.
High-dose albumin treatment for acute ischaemic stroke (ALIAS) Part 2: a randomized, double-blind, phase 3, placebo-controlled trial
Lancet Neurol
(2013) - et al.
Excitotoxicity and stroke: identifying novel targets for neuroprotection
Prog Neurobiol
(2014) - et al.
Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomized, double-blind, placebo-controlled trial
Lancet Neurol
(2012) Towards the physiological function of uric acid
Free Radic Biol Med
(1993)