Anti-inflammatory treatments for stroke: from bench to bedside

Abstract

So far, intravenous tissue-type plasminogen activator (tPA) and mechanical removal of arterial blood clot (thrombectomy) are the only available treatments for acute ischemic stroke. However, the short therapeutic window and the lack of specialized stroke unit care make the overall availability of both treatments limited. Additional agents to combine with tPA administration or thrombectomy to enhance efficacy and improve outcomes associated with stroke are needed. Stroke-induced inflammatory processes are a response to the tissue damage due to the absence of blood supply but have been proposed also as key contributors to all the stages of the ischemic stroke pathophysiology. Despite promising results in experimental studies, inflammation-modulating treatments have not yet been translated successfully into the clinical setting. This review will (a) describe the timing of the stroke immune pathophysiology; (b) detail the immune responses to stroke sift-through cell type; and

Keywords: clinical trial; immunomodulatory drugs; inflammation; stroke models; translation.

Figure 1.

Immune reactions after ischemic stroke. (a) In the intact brain, the functional unit formed by tightly jointed ECs and astrocytic endfeet constitute the BBB, a strong protective blood–tissue barrier from pathogens. Immune cells circulate freely in the blood, and in the brain parenchyma, resting microglia survey the environment with their processes. (b) A few minutes after stroke onset, the BBB is disrupted and local ECs are activated. The tight junctions between ECs disappear and activated ECs express CAMs. This allows white cell rolling and adhesion at the luminal side of the blood vessel and then transmigration from the vascular compartment to the brain parenchyma. Once infiltrated in the tissue, neutrophils secrete pro-inflammatory factors that will recruit monocytes/macrophages, and later lymphocytes to the parenchyma. After stroke, microglia switches from a resting form to an activated state, adopting a phagocytic phenotype and secreting pro-inflammatory factors. BBB, blood–brain barrier; CAM, cellular adhesion molecule; EC, endothelial cell.

Figure 2.

Summary of clinical trials targeting the immune responses triggered after ischemic stroke. CD11/CD18, LFA-1 for lymphocyte function-associated antigen 1; IL-1, interleukin 1; rhIL1-Ra, recombinant human interleukin 1 receptor antagonist; ICAM-1, intercellular adhesion molecule; VCAM-1, vascular cell adhesion molecule; VLA-4, leukocyte very late antigen-4.