Aneurysmal Subarachnoid Hemorrhage and Neuroinflammation: A Comprehensive Review

Abstract

Aneurysmal subarachnoid hemorrhage (SAH) can lead to devastating outcomes including vasospasm, cognitive decline, and even death. Currently, treatment options are limited for this potentially life threatening injury. Recent evidence suggests that neuroinflammation plays a critical role in injury expansion and brain damage. Red blood cell breakdown products can lead to the release of inflammatory cytokines that trigger vasospasm and tissue injury. Preclinical models have been used successfully to improve understanding about neuroinflammation following aneurysmal rupture. The focus of this review is to provide an overview of how neuroinflammation relates to secondary outcomes such as vasospasm after aneurysmal rupture and to critically discuss pharmaceutical agents that warrant further investigation for the treatment of subarachnoid hemorrhage. We provide a concise overview of the neuroinflammatory pathways that are upregulated following aneurysmal rupture and how these pathways correlate to long-term outcomes. Treatment of aneurysm rupture is limited and few pharmaceutical drugs are available. Through improved understanding of biochemical mechanisms of injury, novel treatment solutions are being developed that target neuroinflammation. In the final sections of this review, we highlight a few of these novel treatment approaches and emphasize why targeting neuroinflammation following aneurysmal subarachnoid hemorrhage may improve patient care. We encourage ongoing research into the pathophysiology of aneurysmal subarachnoid hemorrhage, especially in regards to neuroinflammatory cascades and the translation to randomized clinical trials.

Keywords: aneurysmal subarachnoid hemorrhage; cerebral vasospasm; neuroinflammation; novel treatments.

Figure 1

Red blood cell breakdown causes the release of heme, hemin, and methemoglobin. Through interactions with toll-like receptors on microglia, high mobility group box 1 protein is increased. This increase leads to downstream activation of NFκB and the release of proinflammatory cytokines.

Figure 2

Following aneursym rupture, the brain stem can become ischemic and trigger heart damage. Damaged heart tissue can subsequently contribute to the inflammatory milieu following subarachnoid hemorrhage. Inflammation from heart abnormalities triggers the infiltration of peripheral immune cells into the brain as indicated by the arrows. This step-wise process further exacerbates neuroinflammation. Persistent neuroinflammation can lead to long-term cognitive and behavioral deficits.