Abstract
Aneurysmal subarachnoid hemorrhage (aSAH) is a complex and potentially deadly disease. Neurosurgical clipping or endovascular coiling can successfully obliterate ruptured aneurysms in almost every case. However, despite successful interventions, the clinical outcomes of aSAH patients are often poor. The reasons for poor outcomes are numerous, including cerebral vasospasm (CVS), post-hemorrhagic hydrocephalus, systemic infections and delayed cerebral ischemia. Although CVS with subsequent cerebral ischemia is one of the main contributors to brain damage after aSAH, little is known about the underlying molecular mechanisms of brain damage. This review emphasizes the importance of pharmacological interventions targeting high mobility group box 1 (HMGB1)-mediated brain damage after subarachnoid hemorrhage (SAH) and CVS. We searched Pubmed, Ovid medline and Scopus for “subarachnoid hemorrhage” in combination with “HMGB1”. Based on these criteria, a total of 31 articles were retrieved. After excluding duplicates and selecting the relevant references from the retrieved articles, eight publications were selected for the review of the pharmacological interventions targeting HMGB1 in SAH. Damaged central nervous system cells release damage-associated molecular pattern molecules (DAMPs) that are important for initiating, driving and sustaining the inflammatory response following an aSAH. The discussed evidence suggested that HMGB1, an important DAMP, contributes to brain damage during early brain injury and also to the development of CVS during the late phase. Different pharmacological interventions employing natural compounds with HMGB1-antagonizing activity, antibody targeting of HMGB1 or scavenging HMGB1 by soluble receptors for advanced glycation end products (sRAGE), have been shown to dampen the inflammation mediated brain damage and protect against CVS. The experimental data suggest that HMGB1 inhibition is a promising strategy to reduce aSAH-related brain damage and CVS. Clinical studies are needed to validate these findings that may lead to the development of potential treatment options that are much needed in aSAH.
Highlights
Aneurysmal subarachnoid hemorrhage is a devastating cerebrovascular event that accounts for only 5% of all stroke events
high mobility group box 1 (HMGB1) Is Released in Cerebrospinal Fluid (CSF) and Systemic Circulation after aSAH
damage-associated molecular pattern molecules (DAMPs) liberated upon damage to the cells of the CNS will find their way to the CSF as this fluid is immediately in contact with the CNS tissues
Summary
Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating cerebrovascular event that accounts for only 5% of all stroke events. The interaction of DAMPs with receptors such as the receptor for advanced glycation end products (RAGE), the toll-like receptor (TLR)-2 and TLR-4, may initiate and drive the inflammatory response both in the brain parenchyma and cerebral blood vessels; this links EBI with delayed inflammation. It is, important to identify the molecules that initiate and drive the immune response after aSAH. Increasing evidence from experimental and clinical studies has suggested that HMGB1 might be an important target to reduce damage during EBI and life-threatening post-aSAH complications, including CVS. We systematically reviewed the literature on the pharmacological targeting of HMGB1 in aSAH and the criteria for the selection of articles is presented in the Supplementary Materials (Figure S1)
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