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.
Highlights
Delayed cerebral vasospasm (DCV) with subsequent cerebral ischemia, which usually develops 7 to 14 days after subarachnoid hemorrhage (SAH), is one of the major causes of morbidity and mortality in patients with ruptured cerebral aneurysms[1,2]
We demonstrate that treatment with anti-High mobility group box-1 (HMGB1) monoclonal antibody (mAb) dramatically attenuated the progression of delayed cerebral vasospasm (DCV) in a rat SAH model through the inhibition of HMGB1 translocation in arterial smooth muscle cells, suppression of up-regulation of vasocontractile receptors and diminution of vascular inflammatory responses, in association with the improvement of neurological symptoms
Cerebral vasospasm in SAH rats was evaluated by measuring the diameter of the basilar artery (BA) on computed tomographic angiography (CTA) images from the individual rats 48 hr before and after blood injection into the cisterna magna
Summary
Delayed cerebral vasospasm (DCV) with subsequent cerebral ischemia, which usually develops 7 to 14 days after subarachnoid hemorrhage (SAH), is one of the major causes of morbidity and mortality in patients with ruptured cerebral aneurysms[1,2]. Toll like receptors (TLRs), nuclear factor-kappa B (NF-κB), interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) have been shown to participate in the damage-induced inflammatory process after SAH, and to be involved in the breakdown of the blood brain barrier (BBB) in SAH3–7. Inhibitors of these pro-inflammatory factors have been evaluated for their potential neuroprotective effects in experimental animal studies, the relationship between inflammation and cerebral vasospasm is not clearly understood[8,9,10,11,12,13]. These data strongly suggest that HMGB1 may play a crucial role in early brain injury and DCV after SAH
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