Anti-high mobility group box-1 (HMGB1) antibody attenuates delayed cerebral vasospasm and brain injury after subarachnoid hemorrhage in rats

Abstract

Although delayed cerebral vasospasm (DCV) following subarachnoid hemorrhage (SAH) is closely related to the progression of brain damage, little is known about the molecular mechanism underlying its development. High mobility group box-1 (HMGB1) plays an important role as an initial inflammatory mediator in SAH. In this study, an SAH rat model was employed to evaluate the effects of anti-HMGB1 monoclonal antibody (mAb) on DCV after SAH. A vasoconstriction of the basilar artery (BA) associated with a reduction of nuclear HMGB1 and its translocation in vascular smooth muscle cells were observed in SAH rats, and anti-HMGB1 mAb administration significantly suppressed these effects. Up-regulations of inflammation-related molecules and vasoconstriction-mediating receptors in the BA of SAH rats were inhibited by anti-HMGB1 mAb treatment. Anti-HMGB1 mAb attenuated the enhanced vasocontractile response to thrombin of the isolated BA from SAH rats and prevented activation of cerebrocortical microglia. Moreover, locomotor activity and weight loss recovery were also enhanced by anti-HMGB1 mAb administration. The vasocontractile response of the BA under SAH may be induced by events that are downstream of responses to HMGB1-induced inflammation and inhibited by anti-HMGB1 mAb. Anti-HMGB1 mAb treatment may provide a novel therapeutic strategy for DCV and early brain injury after SAH.

HMGB1 a-Box Reverses Brain Edema and Deterioration of Neurological Function in a Traumatic Brain Injury Mouse Model

“…Encouraging results, that have been obtained with HMGB1 antibodies, peptides, natural or synthetic molecules, suggest therapeutic effects of HMGB1 on TBI [27]. HMGB1-specific antibodies have been shown to reduce brain edema, decrease cell apoptosis and improve functional outcomes in intracerebral hemorrhage and TBI rat models [8, 30]. Consistently, pharmacological inhibitors of HMGB1, glycyrrhizin and ethyl pyruvate, have beneficial effects in brain trauma models [31, 32].…”

“…Numerous studies suggest that inhibition of cytokine activities by anti-inflammatory agents, including HMGB1 antibodies, could improve neurological functions in TBI [26, 30]. Administration of anti-inflammatory HMGB1 A-box shortly after injury inhibited IL-1β, IL-6 and TNF-α at 24 h following CCI (Fig.…”

Anti-high mobility group box-1 (HMGB1) antibody inhibits hemorrhage-induced brain injury and improved neurological deficits in rats

“…Our results also suggest that anti-HMGB1 mAb could be a valuable neuroprotective agent for the treatment of ICH, even if the treatment is initiated at 3 h after the onset of hemorrhage. We propose that anti-HMGB1 mAb treatment could be a novel therapeutic strategy applicable for three types of stroke: ICH, brain infarction1112 and subarachnoid hemorrhage40.…”

Can admission lipoprotein-associated phospholipase A2 predict the symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage?

“…Based on published literature, the possible causes of post-aSAH CV include endothelial cell interactions, alterations in calcium signaling, oxidative processes, spreading depolarization, and/or inflammation [29,30]. For goal-oriented therapy, the aim is to create an optimal physiological environment for the comatose injured brain, and technologies such as detection of related biomarkers may eventually be used.…”