inflammation typically follows an orderly process of events involving neurons and neuroglia, vessels, and the circulating blood. Collectively, the ensuing post-ischaemic inflammatory response can be harmful, leading to secondary brain injury. However, post-ischaemic inflammation is a self-limiting process, which, during later stages of the ischaemic injury, is necessary for the removal of dead cells and production of growth factors helping to foster an environment for tissue reconstruction and repair (for review see ANRATHER and IADECOLA 2016). Furthermore, while the immune response starts locally, inflammatory mediators expressed during the early phase of ischaemic damage can propagate through the disrupted blood-brain-barrier (BBB) resulting in a systemic inflammatory response. This, in turn, is followed by an opposing anti-inflammatory response predisposing patients to stroke-induced immunosuppression (for review see: ibid.). Therefore, any therapeutic concept should consider the biphasic nature of post-ischaemic inflammation by attenuating its devastating potential in the acute phase, while enhancing its beneficial contributions to tissue repair during later stages of disease. Emmrich, J. V., Knauss, S., Endres, M., Current advances, challenges, and opportunities in stroke research, management, and care NAL-live 2021.2, v1.0, doi:10.34714/leopoldina_NAL-live_0002_01000 6 Fig. 3 Mechanisms of post-ischaemic damage and protection. The ischaemic cascade is a complex interaction between all cell types of the brain and supplying blood vessels. Permanent injury to brain tissue results from early primary and delayed secondary damage. Necrosis and apoptosis are the main mechanisms of cell death following ischaemic injury. Mild ischaemic injury preferentially induces cell death via apoptotic mechanisms. Apoptosis is the predominant type of cell death in the penumbra. Secondary damage is mostly driven by inflammation through the generation of reactive oxygen species, activation of the complement system, induced apoptosis, and the release of cytotoxic and apoptosis-inducing molecules by cytotoxic T cells and natural killer cells (based on ENDRES et al. 2008). Difficulties in Translating Stroke Research into Clinical Practice Despite numerous neuroprotective agents that have been found to reduce brain injury and improve neurological outcomes in various animal models of stroke, the translation of these benefits from the laboratory bench to the stroke unit, the so-called bench-to-bedside translation, has been dismal. In fact, since the early 1960s more than 1,000 molecules with brain-protective effects relevant to stroke have been identified, leading to the publication of more than 3,500 articles and the implementation of several hundred clinical trials aimed at establishing an effective neuroprotective therapy after stroke (O’COLLINS et al. 2006). However, apart from reperfusion induced through mechanical recanalization or intravenous tissue plasminogen activator, translation into effective therapies has failed. This failure to translate successful preclinical therapeutic candidates into benefits for patients has been described as the translational roadblock or, more dramatically, the translational valley of death, separating the world of preclinical research from clinical benefit. Several reasons for this roadblock and ways to cross the valley of death have been debated in the scientific community but can be regarded along two lines. The first is internal validity. It has been argued that preclinical literature is confounded by factors leading to the overestimation of effect size and identification of false positives. Among the most commonly cited are a prevalence of underpowered studies, lack of measures like randomisation and blinding to reduce bias, and a tendency to avoid the publication of negative findings. According to some meta-analyses, each of these factors can lead to an overestimation of true effect size by 10 – 30 % (CROSSLEY et al. 2008, MACLEOD et al. 2008). At the same time, clinical studies using these false estimates of effect size might be underpowered to detect a true but much smaller effect and thus produce false negatives. The second is external validity in which there is a difference in the stroke models and treatment paradigm in preclinical research and human stroke. One of the most striking differences in many studies comparing preclinical and clinical treatment paradigms is the timing of treatment administration. While most preclinical studies administer treatment at the time the ischaemia occurs or even earlier, reaching the patient in real life within 4.5 hours after the onset of symptoms is a challenge. With the advent of new pre-hospital stroke care models, described in more detail below, ultra-early treatment strategies may, however, be within reach in the near future. In addition, inherent differences in the anatomy and physiology of rodent model organisms and humans contribute to the translational roadblock. Even if a pathomechanism proves translatable from mouse to man, differences in the ability of drugs to cross the much weaker barrier between the blood and the brain tissue in model organisms and the human blood brain barrier may lead to a failure of a potential drug to reach the target tissue. Nevertheless, Emmrich, J. V., Knauss, S., Endres, M., Current advances, challenges, and opportunities in