Evolving Clinical-Translational Investigations of Cerebroprotection in Ischemic Stroke

Abstract

Ischemic stroke is a highly morbid disease, with over 50% of large vessel stroke (middle cerebral artery or internal carotid artery terminus occlusion) patients suffering disability despite maximal acute reperfusion therapy with thrombolysis and thrombectomy. The discovery of the ischemic penumbra in the 1980s laid the foundation for a salvageable territory in ischemic stroke. Since then, the concept of neuroprotection has been a focus of post-stroke care to (1) minimize the conversion from penumbra to core irreversible infarct, (2) limit secondary damage from ischemia-reperfusion injury, inflammation, and excitotoxicity and (3) to encourage tissue repair. However, despite multiple studies, the preclinical-clinical research enterprise has not yet created an agent that mitigates post-stroke outcomes beyond thrombolysis and mechanical clot retrieval. These translational gaps have not deterred the scientific community as agents are under continuous investigation. The NIH has recently promoted the concept of cerebroprotection to consider the whole brain post-stroke rather than just the neurons. This review will briefly outline the translational science of past, current, and emerging breakthroughs in cerebroprotection and use of these foundational ideas to develop a novel paradigm for optimizing stroke outcomes.

Keywords: cerebroprotection; excitotoxicity; inflammation; ischemia-reperfusion injury; ischemic stroke; oxidative stress; stem cells; translational studies.

Figure 1

Current stroke therapies fail to comprehensively address the multifaceted mechanisms underlying ischemic injury and are often associated with unintended consequences or practical limitations. (A) Standard treatment involves thrombolytics (tPA/TNK) +/− endovascular thrombectomy (EVT). It depends upon the time since the patient’s last known normal status, comorbidities, a set of inclusion/exclusion criteria, and considerations of the volume of core versus penumbra. (B) Thrombolytics are intended to promote clot breakdown. However, their lytic action risks downstream clot propagation, endothelial barrier breakdown and subsequent hemorrhage, immune cell plugging, and expansion of the ischemic core due to neuronal effects of tPA. (C) ROS scavengers—NXY-059 in this example—would ideally trap ROS to render them inactive; however, due to excess of ROS creation in the injured brain and impaired penetrance past the blood–brain barrier, the amount of ROS substrate may be too difficult to overcome. (D) Antibodies such as enlimomab and natalizumab target signaling molecules involved in leukocyte recruitment, but redundancy in this pathway may allow for leukocyte extravasation via other adhesion molecules. Consequently, patients may be at risk for worsened post-stroke immunosuppression without affecting leukocyte transendothelial migration. (E) Excitotoxicity inhibitors aim to inhibit neuronal necrosis via antagonism of glutamate receptors. However, excitotoxicity-induced cell death begins within seconds of ischemia, so excitotoxicity inhibitors are delivered too late to mitigate damage. (F) Neural stem cells given intravenously or intrathecally are intended to replace damaged neurons. However, stem cell delivery to the infarcted tissue is suboptimal, with most cells being sequestered in the lungs.

Figure 2

Emerging treatment strategies for stroke management should focus on a combinatorial approach as assessed by the patient’s individualized disease profile. (A) Patient 1displays a high level of coagulation and is, therefore, a candidate for mechanical thrombectomy given their time of presentation. Upon reperfusion, patient 1 demonstrates high glutamate excitotoxicity and inflammation levels, indicating that their individualized treatment plan should include an excitotoxicity inhibitor and an anti-inflammatory component. Patient 2 is not a candidate for either thrombolytic therapy or mechanical thrombectomy, so targeting glutamate excitotoxicity and oxidative stress are not viable options for this patient. Instead, patient 2 displays high levels of microvascular no-reflow, inflammation, and neural network change, suggesting a treatment strategy that may include vasoactive and anti-inflammatory therapies and stem cell administration. Patient 3 presents acutely and is a candidate for thrombolytics but unsuitable for mechanical thrombectomy. Following reperfusion, patient 3 demonstrates high levels of oxidative stress and should also be considered for antioxidant therapy. (B) For instance, patient 1 is at a higher risk for microvascular no-reflow given their pre-existing diabetes, which suggests a potential benefit for adding vasoactive therapy. Patient 2 is relatively young and has no comorbidities, and as a result, may be less likely to require intervention to repair neural networks. Patient 3 has pre-existing hypertension and is thus more likely to display microvascular no-reflow and inflammation, which may necessitate supplemental vasoactive and anti-inflammatory therapy.