Rationale

Normally, cerebral blood flow (CBF) is maintained by cerebral autoregulation at about 50 mL blood/100 g brain/min. In acute ischaemic stroke, a cerebral artery is occluded or there is a reduction in perfusion distal to a severe stenosis, resulting in focal brain ischaemia and infarction. As the regional CBF falls, the regional lack of oxygen and glucose results in a time- and flow-dependent cascade characterized by a fall in energy (adenosine triphosphate [ATP]) production. Neuronal function is affected in two stages. The first threshold is at a blood flow of about 20 mL blood/100 g brain/min, below which neuronal electrical function is compromised, generating clinical deficits, but cellular homeostasis is maintained and recovery remains possible. However, if blood flow falls below the second critical threshold of 10 mL blood/100 g brain/min, an ‘ischaemic cascade’ of injurious molecular events is triggered (Doyle et al., 2008; Sekerdag et al., 2018). Free radicals are generated. There is excessive release and impaired reuptake of excitatory amino acid (EAA) neurotransmitters such as glutamate, causing overstimulation of neuronal glutamate receptors (excitotoxicity), aerobic mitochondrial metabolism fails, inefficient anaerobic metabolism of glucose takes over, and harmful lactic acidosis evolves. Energy-dependent homoeostatic mechanisms of maintaining cellular ions fail, potassium leaks out of cells, and sodium, water, and calcium enter cells, leading to cytotoxic oedema and calcium-induced mitochondrial failure, respectively. If severe ischaemia (blood flow below 10 mL blood/100 g brain/min) is sustained, irreversible neuronal damage occurs and neuronal cell apoptosis and necrosis ensue.

Preclinical and neuroimaging studies indicate that the untreated penumbra deteriorates over time (Bardutzy et al., 2005; Heiss, 2011). This concept is supported by analyses of reperfusion therapies for acute cerebral ischaemia, which showed greater benefits of reperfusion by intravenous thrombolysis and by endovascular mechanical thrombectomy with earlier treatment (Emberson et al., 2014; Saver et al., 2016). Just how long ischaemic human brain may survive, and therefore the time window for therapeutic intervention, varies from individual to individual, reflecting degree of CBF compromise, robustness of collateral flow, differential tolerance of grey and white matter to ischaemia, and additional factors. Within the first 3–6 hours after ischaemia onset, nearly all patients still harbour salvageable tissue; from 6 to 24 hours and beyond, a steadily increasing proportion of patients have no remaining tissue at risk, having completed their strokes, but an important, slower progressing subset of patients still possess rescuable tissues.

Neuroprotective treatments are therapies that interrupt the cellular, biochemical, and metabolic processes that lead to brain injury during or after exposure to ischaemia and encompass a wide array of pharmacological and device interventions that block the molecular elaboration of cellular injury in brain tissues exposed to ischaemic stress (Ovbiagele et al., 2003). Neuroprotective treatments may have some mild potential benefits as standalone therapies in settings in which tissues are exposed to permanent ischaemia. However, the settings in which they are likely to exert their greatest benefit are those in which ischaemia will be transient, and neuroprotective interventions can enable ischaemic tissues to tolerate the ischaemic insult until the ischaemia is relieved. A major potential role of neuroprotective therapies is in spontaneous ischaemic stroke, where they can support the ischaemic penumbra until CBF is restored by intravenous thrombolysis and/or endovascular mechanical thrombectomy. They also could be helpful during surgical and endovascular procedures in which the brain is exposed to ischaemia for a delimited period of time.

Although numerous neuroprotective agents have been found beneficial in various preclinical stroke models, successful translation to human stroke patients has been challenging. Over 100 neuroprotective interventions showing signals of effect in preclinical stroke models have been advanced to human clinical trial testing and none was found to be of definite proven benefit (O’Collins et al., 2006; Hong et al., 2011). Several deficiencies in preclinical study and clinical trial designs have been identified as likely contributing to this breakdown in translation (Ovbiagele et al., 2003; O’Collins et al., 2006; Fisher et al., 2009; Lapchak et al., 2013). Preclinical experimental studies have often failed to use robust randomization and blinding techniques to avert bias, started treatments much earlier than achievable in the human clinical setting, and tested agents in young, otherwise healthy rodents and other species rather than older animals with multiple comorbidities. Human clinical trials have often failed to start therapies in the very first minutes and hours after onset, when treatment effect would be maximal, and to confine enrolment to patients likely to have transient rather than permanent ischaemic exposure.

The promise of, and the need for, effective brain cytoprotection remains great, despite past disappointments in neuroprotective development programmes. Reperfusion therapies, which require brain imaging and transport to a treatment-capable centre prior to start, will always have their treatment benefit constrained by the brain injury that accumulates before they can be initiated. For example, in pivotal trials, endovascular mechanical thrombectomy tremendously improves patient outcomes compared with no endovascular intervention, and yet 73% of the patients treated with endovascular therapy still have disabled (modified Rankin Scale [mRS] 2–6) outcomes at 3 months. Neuroprotective agents, many of which are safe and potentially beneficial for haemorrhagic as well as ischaemic stroke, could be started much earlier than reperfusion therapies, in the ambulance or self-administered at home, preserving more brain in a salvageable state until reperfusion can be achieved, potentially substantially magnifying the benefit of CBF restoration. Given the robust signals of benefit of neuroprotection in preclinical focal ischaemic stroke models and the demonstrated benefit of neuroprotection with hypothermia in human global brain ischaemia, there is excellent reason to hope that improved preclinical and clinical study designs will yield clinically useful agents for human stroke.

Among the many classes and individual examples of neuroprotective agents that have been tested in ischaemic stroke, this chapter will review several of the most studied and most promising. A broad mechanistic classification of neuroprotective interventions, with listing of several individual agents, is shown in Table 12.1, and includes: (1) Metabolism Suppressors, (2) Promoters of Genetically Programmed Hypoxia/Injury Tolerance, (3) Free Radical Scavengers and Anti-Oxidants, (4) Promoters of Membrane Repair, (5) Modulators of Excitatory Amino Acids, (6) Modulators of Calcium Influx, (7) Sodium Channel Blockers, (8) Modulators of GABA Inhibition, (9) Nitric Oxide Donors, (10) Modulators of Carnitine + Mitochondrial Function, (11) Anti-Inflammatory, (12) Oxygen Delivery Enhancers, (13) Agents with Multiple Leading Mechanisms, and (14) Uncertain Mechanism.

Hypothermia

Hypothermia is a quintessentially pleiotropic neuroprotective intervention, concurrently inhibiting many of the molecular pathways that elaborate ischaemic injury to neural tissues (Kurisu and Yenari, 2018). Hypothermia decreases the cerebral metabolic rate and metabolic demand, reducing the mismatch between energy supply and energy demand. Hypothermia additionally reduces free radical production, excitotoxicity, apoptosis, and inflammation. Mild (35–36°C), moderate (32–34°C), and profound (<32°C) hypothermia all have protective effects in preclinical models of ischaemic stroke. Achieving profound hypothermia in human patients requires intubation and sedation, to prevent shivering and respiratory compromise. Moderate hypothermia, however, can be achieved in awake patients with concomitant medications to reduce shivering.

Profound hypothermia is already routinely applied to counter the effects of cerebral hypoxia in neurosurgery and open-heart surgery. In cardiac arrest with global brain ischaemia, moderate (32–33°C) hypothermia improves outcome (Arrich et al., 2016). In acute stroke, a high body temperature has been associated with a worse prognosis (Marehbian and Greer, 2017) (see Chapter 5), but it is not known if lowering temperature improves prognosis. Some temperature-lowering agents, like non-steroidal anti-inflammatory drugs, have antiplatelet activity and could increase the risk of bleeding in acute ischaemic and haemorrhagic stroke. Other risks associated with induced hypothermia are mainly sepsis, pneumonia, and coagulopathy.

Evidence

Hypothermia as a neuroprotective intervention for acute ischaemic stroke has largely been evaluated in small randomized trials designed to develop and validate technically effective regimens for rapid and sustained cooling to targeted temperature and control of shivering, using both surface cooling and indwelling vascular cooling devices. With more recent regimens, rapid attainment and tight maintenance of targeted moderate hypothermia in awake patients has been achieved, and absence of major adverse interaction with intravenous thrombolysis demonstrated. However, in these feasibility and regimen optimization studies, time from onset to enrolment and to time of first achievement of cerebral hypothermia has been prolonged. A meta-analysis of 6 randomized trials enrolling a total of 311 patients does not show a difference in the frequency of disability-free (mRS 0–1) outcome with hypothermia versus control, 25.9% versus 29.6%, risk ratio (RR) 0.88 (95% confidence interval [CI]: 0.64–1.47) (Figure 12.1) (Wan et al., 2014; Lyden et al., 2016).

Figure 12.1 Forest plot showing the effects of hypothermia vs control for acute ischaemic stroke on freedom from disability (mRS 0–1) at long-term follow-up.

Hypothermia has also been studied as an anti-oedema therapy for malignant middle cerebral artery infarction, as reviewed in Chapter 11.

Adverse Effects

Across the 6 randomized trials of hypothermia in human focal ischaemic stroke, mortality did not differ between treated and control groups. An increased risk of pneumonia was observed, 20.0% versus 7.6% (RR 2.65; 95% CI: 1.45–4.83). No differences were found for symptomatic intracerebral haemorrhage (SICH), fatal intracerebral haemorrhage (ICH), deep vein thrombosis (DVT), or atrial fibrillation.

Ischaemic Conditioning

In ischaemic conditioning, an organ is exposed to one or more brief, non-lethal cycles of ischaemia and reperfusion, activating endogenous cellular protective pathways rendering the target organ more tolerant of prolonged ischaemia. The intermittent ischaemia challenges can occur directly to the target organ; for example, transient ischaemic attacks may render the brain more resistant to subsequent infarction. But the intermittent ischaemia challenges may also be delivered to remote sites, typically simply by intermittent inflation of a blood pressure cuff placed on one or more limbs, with induction of humoral signals that activate hypoxia resistance pathways throughout the body, including the brain (Hess et al., 2015).

In various preclinical models, remote ischaemic conditioning has been found to reduce brain injury when applied before (pre-conditioning), during (per-conditioning), and soon after (post-conditioning) the cerebral ischaemic insult (Wang et al., 2015). Several molecular mechanisms appear to contribute to cerebral ischaemic conditioning, including: (1) increasing antioxidant production and increasing DNA repair capacity; (2) anti-excitotoxic effects by inhibiting glutamate and increasing gamma-aminobutyric acid (GABA) release; (3) anti-inflammatory effects by stimulating Toll-like receptors, which activate proinflammatory pathways; (4) prevention of mitochondrial-dependent cell death pathways; and (5) release of adenosine and activation of adenosine A1 receptors (Narayanan et al., 2013).

Growth Factors

Growth factors are proteins that regulate the differentiation, survival, and proliferation of neurones, glia, fibroblasts, endothelial cells, and other cell types. Basic fibroblast growth factor (bFGF) promotes neuronal sprouting and proliferation of capillaries and glia during stroke recovery, facilitating neural repair and functional recovery (Paciaroni and Bogousslavsky, 2011). In addition, in stroke models, bFGF initiates a signal transduction cascade, resulting in the expression of cytoprotective genes and their proteins, facilitating cell survival, and reducing infarct volume.

Free Radical Scavengers and Antioxidants

Free radical, reactive oxygen and nitrogen species are produced by cellular enzymes in settings of oxidative stress, including ischaemia, and damage cellular integrity. Enzymatic and non-enzymatic antioxidant molecules react in one-electron reactions with free radicals to avert oxidative damage (Davis and Pennypacker, 2017).

Promoters of Membrane Repair

Citicoline

Citicoline (or cytidine-5′-diphosphoholine, CDP-choline) is an intermediate metabolite in membrane phosphatide biosynthesis, normally present in all cells in the body. In preclinical models, exogenously administered citicoline promotes rapid repair of injured cell surface and mitochondrial membranes and maintenance of cell integrity and bioenergetic capacity, downregulates phospholipases to avert apoptotic and necrotic cell death, and reduces free fatty acid release and ensuing generation of injurious free radicals (Saver, 2008).

Evidence

A meta-analysis identified 10 randomized trials of citicoline in ischaemic stroke, enrolling 4420 patients (Secades et al., 2016) The preponderance of trials enrolled patients within 24–48 hours of onset, with 2 trials enrolling 305 patients (7%) having longer enrolment windows of 7–14 days. Few patients in any trial were enrolled in the first few hours of onset; in the largest ICTUS trial, which had a 24-hour enrolment window, the median time from onset to enrolment was 6.7 hours (Dávalos et al., 2012). Across trials, study treatment was administered for up to 10 days to 6 weeks, and doses ranged from 500–2000 mg daily.

Functional Independence

Across the 10 trials, treatment with citicoline was associated with an increased frequency of functional independence (mRS 0–2 or nearest equivalent) at long-term follow-up, 36.4% versus 31.6%, RR (random effect) 1.20 (95% CI: 1.05–1.55), p = 0.02 (Figure 12.3). However, substantial heterogeneity was noted, I² = 68%, and funnel plot analysis showed some asymmetry suggesting potential publication bias with under-reporting of smaller, nonpositive or less positive trials. The largest and most recent trial, ICTUS, enrolled 2298 patients, accounting for 52% of all patients in the 10-trial meta-analysis, and had neutral results (Dávalos et al., 2012).

Figure 12.3 Forest plot showing the effects of citicoline vs control for acute ischaemic stroke for functional independence (mRS 0–2 or nearest equivalent) at long-term follow-up.

Safety

None of the trials reported any adverse events occurring more frequently in the citicoline than the control groups.

Subgroups

In the large ICTUS trial, enrolling 2298 patients, overall results were neutral on the primary endpoint of recovery at 90 days, measured by a global test combining three measures of success, mRS ≤ 1, National Institutes of Health Stroke Scale (NIHSS) ≤ 1, and Barthel Index ≥ 95, with OR 1.03 (95% CI: 0.86–1.25; p = 0.36). However, heterogeneity of effect was noted for 3 of the 5 prespecified subgroups, with signals of greater benefit and less harm among patients over versus under age 70, p_interaction = 0.001, patients with less initial deficit severity (NIHSS 8–14 vs 15–22 and 22–42), p_interaction = 0.02, and patients ineligible for IV tPA, p_interaction = 0.04. Nonetheless, none of the better performing subgroup categories showed nominally significant benefit: age above 70 (OR 1.17, 95% CI: 0.82–1.50); lesser presenting deficit, (NIHSS 8–14, OR 1.08, 95% CI: 0.86–1.35); and IV tissue plasminogen activator (tPA) ineligible (OR 1.11, 95% CI: 0.85–1.46).

Comment

Current randomized trial evidence largely addresses relatively late start and prolonged continued administration of citicoline, and thus evaluates more for potential subacute neuroreparative than acute neuroprotective treatment effects. The trials have demonstrated agent safety but provide mixed indications of potential benefit. Evidence of potential publication bias and neutral results in the largest single trial indicate caution when interpreting the mild favourable effect seen in meta-analytic summary of all trials. Brief administration of citicoline during the first few hours after onset, until reperfusion is achieved, is a strategy not yet explored in human clinical trials of citicoline. The greater signal of potential benefit observed in the large ICTUS trial among patients with older age and moderately severe rather than extremely severe presenting deficits perhaps hints at beneficial neuroreparative effects among patients with less intrinsic neuroplasticity (older age) and more intact brain systems to recruit into recovery pathways (less severe deficits). However, further, larger trials in these patient groups are needed before firm conclusions can be reached regarding potential agent benefit.

Excitatory Amino Acid Antagonists

Focal cerebral ischaemia causes excess release of EAA neurotransmitters, particularly glutamate, from pre-synaptic vesicles and prevents normal reuptake of glutamate, resulting in very high synaptic concentrations. Glutamate is toxic in neuronal cell culture and in vivo. It acts at post-synaptic receptors, notably the N-methyl-d-aspartate (NMDA) receptor complex (to promote entry of calcium and sodium into neurones) and the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor (to promote principally sodium entry). Resultant cellular depolarization and calcium overload activate intracellular second messenger systems with consequent cell death.

In preclinical models of stroke, antagonists of glutamate release or of postsynaptic glutamate receptors substantially reduce the volume of histological neuronal infarction and improve functional recovery, even when administered up to several hours after the onset of ischaemia (Muir and Lees, 2003). Drugs that modulate EAA toxicity (EAA antagonists) encompass a diversity of pharmacological agents and a number of potential mechanisms of action, including principally inhibition of glutamate release, NMDA receptor antagonism, and AMPA receptor antagonism. The NMDA receptor itself has several modulatory sites that are amenable to pharmacological modification. However, despite multiple supportive studies in preclinical models and advance of many EAA antagonists into human clinical trials, no agent has yet been proven beneficial in acute ischaemic stroke. This section will briefly survey early studied molecular agents and then provide further details on agents of more recent interest.

Evidence

A systematic review analysed RCTs of EAA antagonists and related agents in acute stroke completed by 2001 (Muir and Lees, 2003). Restricting consideration to agents that had EAA antagonism as their leading or co-leading mechanism, there were 33 completed RCTs evaluating 13 agents. Eight agents were 8 NMDA receptor antagonists, 2 AMPA receptor antagonists, 2 agents that were both sodium channel blockers (reducing glutamate release) and also active calcium channel or cyclic guanosine-3′,5′-monophosphate (cGMP) nitric oxide pathway inhibitors, and 1 agent that was both an NMDA receptor antagonist and a sodium channel inhibitor. Time to treatment averaged under 5 hours in many trials, although only a minority of patients were treated in 3 hours or less after stroke onset.

Death or Dependency

A total of 23 randomized trials testing 10 agents and enrolling 9762 patients provided data on death or dependency at long-term follow-up (Figure 12.4). Random allocation to an EAA antagonist was associated with no significant effect on death or dependency at final follow-up compared with control (53.1% vs 51.7%, OR 1.06; 95% CI: 0.98–1.15). There was moderate heterogeneity across agents, I² = 44%.

Figure 12.4 Forest plot showing the effects of excitatory amino acid inhibitors vs control for acute ischaemic stroke on death or dependency at long-term follow-up in RCTs reported between 1984 and 2001 (primarily 1995–2001).

Reproduced from Muir and Lees (2003), with permission from John Wiley & Sons Limited. Copyright Cochrane Library.

Death

Random allocation to an EAA antagonist was associated with no significant effect on death at final follow-up compared with control (20.7% vs 19.6%, OR 1.02, 95% CI: 0.92–1.12) (Figure 12.5). There was only mild heterogeneity across study agents, I² = 20%.

Figure 12.5 Forest plot showing the effects of excitatory amino acid inhibitors vs control for acute ischaemic stroke on death at long-term follow-up in RCTs reported between 1984 and 2001 (primarily1995–2001).

Reproduced from Muir and Lees (2003), with permission from John Wiley & Sons Limited. Copyright Cochrane Library.

NA-1

NA-1 is a cell-permeant eicosapeptide that perturbs the protein–protein interactions of PSD-95, a postsynaptic scaffolding protein that links NMDA glutamate receptors to neurotoxic signalling pathways, including neuronal nitric oxide synthase, a free radical generator. NA-1 reduced infarct size in rodent and primate ischaemic stroke models.

Calcium Channel Antagonists

Massive calcium influx into ischaemic brain cells is a final common pathway leading to cell death, and agents that reduce calcium overload lower infarct volumes in preclinical stroke models (Doyle et al., 2008; Sekerdag et al., 2018). Furthermore, the calcium channel agent nimodipine was shown to be effective in decreasing the occurrence of death and disability after aneurysmal and traumatic subarachnoid haemorrhage (SAH) in humans, likely at least in part by conferring neuronal protection against ischaemic injury arising from delayed cerebral vasospasm (see Chapter 14). Nimodipine and other calcium antagonists can act as neuroprotective drugs by diminishing the influx of calcium ions through the voltage-sensitive calcium channels.

Evidence

A systematic review identified 34 RCTs evaluating 6 calcium antagonist agents in 7731 patients predominantly with ischaemic stroke (but some with haemorrhagic stroke and some with no imaging to confirm stroke subtype), with nimodipine being the most predominantly studied agent (Zhang et al., 2012). The trials more closely evaluated calcium channel antagonism in the subacute rather than acute period. Entry windows were typically up to 24–72 hours post-onset; onset time in some trials may have been the time symptoms were first observed rather than time last known well; the study agent typically was continued for 3–21 days; and the first dose was often given orally, resulting in delayed peak serum levels.

Death or Dependency

Data regarding death or dependency at the end of follow-up were available from 22 RCTs evaluating 3 calcium antagonist agents in 6684 patients. The most common agent studied was nimodipine, evaluated in 19 of the trials and 91% (6093/6684) of the patients. Overall, a possible small detrimental effect of calcium antagonists was noted, 46.6% versus 41.5% (RR 1.05; 95% CI: 0.98–1.13; p = 0.16) (Figure 12.6). There was no evidence of heterogeneity by agent (I² = 0%) but mild heterogeneity by individual trial was noted (I² = 29%).

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Chapter 5 – Supportive Care during Acute Cerebral Ischaemia Chapter 9 – Acute Antiplatelet Therapy for the Treatment of Ischaemic Stroke and Transient Ischaemic Attack Chapter 13 – Acute Treatment of Intracerebral Haemorrhage Chapter 19 – Long-term Antithrombotic Therapy for Large and Small Artery Occlusive Disease Chapter 25 – Using Pharmacotherapy to Enhance Stroke Recovery Chapter 26 – Electrical and Magnetic Brain Stimulation to Enhance Post-stroke Recovery

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