Elsevier

The Lancet Neurology

Volume 15, Issue 8, July 2016, Pages 869-881
The Lancet Neurology

Personal View
Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation

https://doi.org/10.1016/S1474-4422(16)00114-9Get rights and content

Summary

Treatments for acute ischaemic stroke continue to evolve after the superior value of endovascular thrombectomy was confirmed over systemic thrombolysis. Unfortunately, numerous neuroprotective drugs have failed to show benefit in the treatment of acute ischaemic stroke, making the search for new treatments imperative. Increased awareness of the relevance of rigorous preclinical testing, and appropriate selection of study participants, might overcome the barriers to progress in stroke research. Relevant areas of interest include the search for safe and effective treatment strategies that combine neuroprotection reperfusion, better use of advanced brain imaging for patient selection, and wider implementation of prehospital conducted clinical trials. Randomised controlled trials of combination treatments completed within the past 5 years have included growth factors, hypothermia, minocycline, natalizumab, fingolimod, and uric acid; the latter two drugs with alteplase produced encouraging results. Blocking of excitotoxicity is also being reassessed in clinical trials with new approaches, such as the postsynaptic density-95 inhibitor NA-1, or peritoneal dialysis to remove excess glutamate. The findings of these randomised trials are anticipated to improve treatment options and clinical outcomes in of patients with acute stroke.

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

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,

References (113)

  • GL Squadrito et al.

    Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid

    Arch Biochem Biophys

    (2000)
  • Á Chamorro et al.

    Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial

    Lancet Neurol

    (2014)
  • M Willmot et al.

    A systematic review of nitric oxide donors and L-arginine in experimental stroke; effects on infarct size and cerebral blood flow

    Nitric Oxide

    (2005)
  • JM Pocock et al.

    Neurotransmitter receptors on microglia

    Trends Neurosci

    (2007)
  • X Urra et al.

    Harms and benefits of lymphocyte subpopulations in patients with acute stroke

    Neuroscience

    (2009)
  • L Di Menna et al.

    Fingolimod protects cultured cortical neurons against excitotoxic death

    Pharmacol Res

    (2013)
  • CA Dinarello et al.

    Treating inflammation by blocking interleukin-1 in humans

    Semin Immunol

    (2013)
  • VL Feigin et al.

    Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010

    Lancet

    (2014)
  • EH Lo et al.

    Exciting, radical, suicidal: how brain cells die after stroke

    Stroke

    (2005)
  • VE O'Collins et al.

    1,026 experimental treatments in acute stroke

    Ann Neurol

    (2006)
  • SM Rothman et al.

    Glutamate and the pathophysiology of hypoxic–ischemic brain damage

    Ann Neurol

    (1986)
  • Tissue plasminogen activator for acute ischemic stroke

    N Engl J Med

    (1995)
  • JA Zivin et al.

    Tissue plasminogen activator reduces neurological damage after cerebral embolism

    Science

    (1985)
  • J Minnerup et al.

    Analysis of early phase and subsequent phase III stroke studies of neuroprotectants: outcomes and predictors for success

    Exp Transl Stroke Med

    (2014)
  • DJ Gladstone et al.

    Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions

    Stroke

    (2002)
  • DJ Cook et al.

    Translating promising preclinical neuroprotective therapies to human stroke trials

    Expert Rev Cardiovasc Ther

    (2011)
  • C Leiva-Salinas et al.

    Prediction of early arterial recanalization and tissue fate in the selection of patients with the greatest potential to benefit from intravenous tissue-type plasminogen activator

    Stroke

    (2016)
  • JD Fiels et al.

    Meta-analysis of randomized intra-arterial thrombolytic trials for the treatment of acute stroke due to middle cerebral artery occlusion

    J Neurointerv Surgery

    (2011)
  • JM Wardlaw et al.

    Thrombolysis (different doses, routes of administration and agents) for acute ischemic stroke

    Cochrane Database Syst Rev

    (2013)
  • J Nam et al.

    Intra-arterial thrombolysis vs. standard treatment or intravenous thrombolysis in adults with acute ischemic stroke: a systematic review and meta-analysis

    Int J Stroke

    (2015)
  • WJ Powers et al.

    2015 American Heart Association/American Stroke Association Focused update of the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment: a guideline for healthcare professionals from the American Heart Association/American Stroke Association

    Stroke

    (2015)
  • TG Jovin et al.

    Thrombectomy within 8 hours after symptom onset in ischemic stroke

    N Engl J Med

    (2015)
  • JL Saver et al.

    Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke

    N Engl J Med

    (2015)
  • M Goyal et al.

    Randomized assessment of rapid endovascular treatment of ischemic stroke

    N Engl J Med

    (2015)
  • BC Campbell et al.

    Endovascular therapy for ischemic stroke with perfusion-imaging selection

    N Engl J Med

    (2015)
  • OA Berkhemer et al.

    A randomized trial of intraarterial treatment for acute ischemic stroke

    N Engl J Med

    (2015)
  • CK Yarbrough et al.

    Endovascular thrombectomy for anterior circulation stroke: systematic review and meta-analysis

    Stroke

    (2015)
  • CS Kidwell et al.

    A trial of imaging selection and endovascular treatment for ischemic stroke

    N Engl J Med

    (2013)
  • BK Menon et al.

    Role of imaging in current acute ischemic stroke workflow for endovascular therapy

    Stroke

    (2015)
  • P Lipton

    Ischemic cell death in brain neurons

    Physiol Rev

    (1999)
  • ES Flamm et al.

    Free radicals in cerebral ischemia

    Stroke

    (1978)
  • T Nishi et al.

    Superoxide dismutase 1 overexpression reduces MCP-1 and MIP-1 alpha expression after transient focal cerebral ischemia

    J Cereb Blood Flow Metab

    (2005)
  • GJ del Zoppo et al.

    Cerebral microvessel responses to focal ischemia

    J Cereb Blood Flow Metab

    (2003)
  • JP Tsai et al.

    Reperfusion versus recanalization: the winner is

    Stroke

    (2015)
  • A Ames et al.

    Cerebral ischemia. II. The no-reflow phenomenon

    Am J Pathol

    (1968)
  • GJ del Zoppo et al.

    Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons

    Stroke

    (1991)
  • GC Jickling et al.

    Targeting neutrophils in ischemic stroke: translational insights from experimental studies

    J Cereb Blood Flow Metab

    (2015)
  • CN Hall et al.

    Capillary pericytes regulate cerebral blood flow in health and disease

    Nature

    (2014)
  • M Yemisci et al.

    Pericyte contraction induced by oxidative–nitrosative stress impairs capillary reflow despite successful opening of an occluded cerebral artery

    Nat Med

    (2009)
  • J Kuroda et al.

    Nox4 is a major source of superoxide production in human brain pericytes

    J Vasc Res

    (2014)
  • Cited by (0)

    View full text