Treatment of acute ischemic stroke: role of ischemic tolerance in intravenous and endovascular therapies

At present, the most effective breakthrough in the treatment of cerebral ischemia is the successful establishment of systemic thrombolysis and, currently, it is the only US FDA-approved therapy [1,2]. Recently, intravenous and endovascular treatment modalities have gained much attention because of the European Cooperative Acute Stroke Study (ECASS), which concluded that an extension of the therapeutic window could be established for patients with acute ischemic stroke treated with intravenous alteplase (recombinant tissue plasminogen activator [rtPA]) up to 4.5 h after initial onset of symptoms, which may be beneficial [3]. This concept is, of course, not entirely new, but is now confirmed by a prospective, double-blinded randomized study. In practical terms, however, the main problem remains, since only a minor proportion of all stroke patients can profit from such intravenous and endovascular treatment options [4]. Further compounding this type of intervention is the risk of symptomatic intracerebral hemorrhage, which seems to be increased with rtPA treatment, particularly in patients treated between 5 and 6 h after onset [4]. Therefore, the sole extension of the time window with the rtPA treatment does not appear to be beneficial. These facts clearly indicate that increasing our knowledge on the cellular and molecular mechanisms leading to ischemia-related cell damage, combined with strategies based on thrombolysis, might lead us to supplementary therapies that may arise from the field of endogenous neuroprotection. This approach appears promising and may lead to the development of new additional treatments/drugs [5,6].

In fact, cerebral ischemia triggers a number of pathophysiological and biochemical changes in the brain, which present potential targets for therapeutic intervention [6,7]. Abrupt deprivation of oxygen and glucose to neuronal tissues elicits a series of pathologic cascades, leading to the spread of neuronal death [6]. Numerous candidate pathways have been identified [6,8,9]. Several neuroprotective agents that block cell-death pathways have been proposed to have therapeutic potential in patients with stroke [6,8,10] and are the outgrowth of 30 years of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection [8–10]. Such rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade neuroprotection of the ischemic brain may be an achievable goal [8,10]. To date, approximately 160 clinical trials of neuroprotection for ischemic stroke have been initiated [8]. Of the approximate 120 completed trials, two-thirds were smaller early-phase safety–feasibility studies [8]. The remaining were typically larger (>200 subjects) Phase II or III trials but, disappointingly, in less than half of these studies, the neuroprotective therapy was administered within the 4–6-h therapeutic window within which efficacious neuroprotection is considered to be achievable [8].

Another approach to counteract cerebral ischemia–reperfusion injury is hypothermia [11]. The neuroprotective effect of mild hypothermia is a consistent finding in experimental studies and even in some clinical circumstances (e.g., after cardiac arrest and in pediatric cases) [12]. However, its beneficial effect in the treatment of acute ischemic stroke remains controversial [12,13]. Although it may provide a benefit theoretically, Den Hertog et al. recently reported that there is currently no evidence from randomized trials to support routine use of physical or pharmacological strategies to reduce temperature in patients with acute stroke [13].

Further large, randomized clinical trials are warranted to test whether mild hypothermia in combination with a pharmacological neuroprotective agent and rtPA provide synergistic or additive efficacy. In theory, such a combined neuroprotective strategy would further expand the time window in which cerebral revascularization would be of benefit for the patient [11]. Development of such strategies may compare well to other strategies that can be used in daily clinical work (e.g., ischemic tolerance), for example, in organ transplantation. In fact, such combination therapy (mild hypothermia with cellular protection) is a research focus in this field. Over several decades, this research has progressively enabled the possible ischemic time to be extended. Presently, it has found its way into clinical practice and made the improvement in clinical outcome possible [14–16].

Finally, improvements and widespread use of multimodal imaging, such as MRI or CT scans, enabled rapid assessment of the infarct core, penumbra, site of vessel occlusion and/or tissue hemorrhagic propensity, which will undoubtedly improve patient selection with respect to reperfusion therapy beyond any arbitrary fixed time window in the near future. Of course, medical-care professionals and researchers have to be aware that other, nonmedical strategies, such as the development of a sufficiently dense network of ‘stroke units’ or the use of ‘mobile stroke units’ with integrated CT, may improve the management of acute ischemic stroke with the therapeutics that are already available. However, this topic goes beyond the scope of this journal and, undoubtedly, the development of neuroprotective strategies will also be profitable, despite the aforementioned infrastructural and logistical improvements.

In conclusion, understanding ischemic tolerance in its different facets is a good way to unravel the molecular mechanisms involved in neuroprotection and might improve therapeutic strategies and extend the therapeutic window for patients with stroke or other ischemia-related diseases.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.