Tolga D Dittrich, MD
@to_dittrich
Over the past years, research has yielded several interesting new insights into the role of inflammation in the different stages of cerebrovascular injury. The development of therapeutic approaches is still in its beginning. It ranges from broadly effective anti-inflammatory agents to very specific drugs that interfere with the signaling pathways of the inflammatory cascade. This comprehensive article by Mun and Hinman presents the current state of knowledge on fundamental inflammatory mechanisms associated with cerebrovascular injury and illustrates the role of inflammation as a therapeutic target.
The immunological mechanisms underlying cerebrovascular injury are incredibly complex. Both intravascular and parenchymal inflammatory processes are driven by the invasion of inflammatory cells (e.g., neutrophil granulocytes) and the release of humoral factors (e.g., cytokines, complement factors, and acute-phase proteins) and may lead to the formation of microvascular thrombi and vascular leaks.
At the level of classical vascular risk factors leading to the development and accumulation of chronic cerebrovascular injury, the idea of underlying chronic inflammation has existed for some time. This concept is supported by several longitudinal studies that have examined blood biomarkers. C-reactive protein (CRP) is among these biomarkers representing the postulated proinflammatory milieu. Elevated CRP levels have been associated with adverse effects on white matter structural integrity and increased risk of recurrent microangiopathic stroke.
But these findings could be of clinical relevance for the future treatment of ischemic stroke. There is emerging evidence that neutrophil granulocytes can negatively affect cerebral microcirculation. Some patients do not show clinical improvement despite rapid, successful restoration of the macrocirculation. One possible explanation is the concept of continued impaired microcirculation (also referred to as the no-reflow phenomenon). In mouse models with an established no-reflow phenomenon, it has been shown that induction of neutropenia led to a reduction of infarct volume with a consecutive improvement of outcome. Moreover, the complement system plays an essential role throughout the course of ischemic stroke. For one, animal models have shown that treatment with complement factor 3 (C3) activation inhibitors was associated with improved outcome. Conversely, C3a is also known to play a critical role in poststroke recovery, highlighting the double-edged nature of potential inhibition therapies.
In summary, several points can be made. First, further characterization and improvement of the understanding of inflammatory and immune processes form the cornerstone for the development of anti-inflammatory strategies in preventing, treating, and regenerating vascular brain injury. Second, for the future broad or specific anti-inflammatory therapies, the timing of intervention in the inflammatory cascade and the consideration of interactions are of great importance. Third, experimental animal models have shown promising targets for potential therapeutic agents. However, when translated to humans, only a few compounds have shown promising results so far.
