Targeting High Mobility Group Box 1 in Subarachnoid Hemorrhage: A Systematic Review

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.

Inflammation and Anti-Inflammatory Targets after Aneurysmal Subarachnoid Hemorrhage

“…Rupture of an intracranial aneurysm causes blood to pour in subarachnoid space and leads to a transient increase in global intracranial pressure (ICP). This transient elevated ICP may lead to the release of molecules from damaged brain tissue [ 11 , 15 ]. Molecules from extravasated blood and from damaged brain, being the earliest events in the pathophysiology, seem to be the key initiators of the inflammatory cascade, including the expression of adhesion molecules and infiltration of immune cells (specifically macrophages) [ 11 , 13 , 15 ].…”

“…This transient elevated ICP may lead to the release of molecules from damaged brain tissue [ 11 , 15 ]. Molecules from extravasated blood and from damaged brain, being the earliest events in the pathophysiology, seem to be the key initiators of the inflammatory cascade, including the expression of adhesion molecules and infiltration of immune cells (specifically macrophages) [ 11 , 13 , 15 ]. Infiltrated leukocytes and activated resident microglia start the inflammatory cascade, leading to the release of different inflammation-related cytokines [ 16 ].…”

“…Infiltrated leukocytes and activated resident microglia start the inflammatory cascade, leading to the release of different inflammation-related cytokines [ 16 ]. This vicious cycle of inflammation probably contributes to almost all mechanisms in the course of aSAH, including apoptotic or necrotic cell death, cortical spreading depression (CSD), blood–brain barrier (BBB) disruption, microthrombosis, cerebral vasospasm (CVS), delayed cerebral ischemia (DCI), hydrocephalus, epilepsy, and multiple organ infections [ 3 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Hydrocephalus after aneurysmal subarachnoid hemorrhage: Epidemiology, Pathogenesis, Diagnosis, and Management

“…The oozing blood and its degradation products also damage various cells in the surrounding area, releasing DAMPs [75]. The over-expression of the mediators (IL-1, IL-6, and TNF-β) and receptors (TLR-2/4, receptors for advanced glycation end-products) activates the destruction and repair process [76]. Sun et al reported data showing that HMGB1 translocations precede other cytokine increase, HMGB1 may be an early upstream promoter of inflammatory response after SAH.…”

Role of Adaptor Protein Myeloid Differentiation 88 (MyD88) in Post-Subarachnoid Hemorrhage Inflammation: A Systematic Review

“…The toxic effects of the blood and its degradation products further add to the injury of the brain [1,6]. There is a considerable body of evidence suggesting that during this insult, several damage-associated molecular patterns (DAMPs) are liberated from various cellular compartments, which have the capacity to upregulate inflammation after ligation of their cognizant pattern recognition receptors (PRR) [7][8][9][10][11]. Over the past few years, the concept of early brain injury and delayed brain injury has evolved to consider the events triggered immediately after the sentinel bleed up to 72 h and over 3-14 days or more, respectively [1,6,12,13].…”