Therapeutic effect of anti-HMGB1 antibody in a mouse model of 4-h middle cerebral artery occlusion: comparison with tissue plasminogen activator

Objective Delayed tissue plasminogen activator (tPA) treatment increases the risk of intracerebral hemorrhage in patients with ischemic stroke. We previously demonstrated that tPA treatment caused hemorrhagic complications in a 4-h middle cerebral artery occlusion (MCAO) mouse model when administered after reperfusion. In the present study, we administered an anti-high mobility group box 1 (alpha HMGB1) antibody to 4-h MCAO mice to evaluate the usability of alpha HMGB1 antibody treatment in the delayed phase of ischemia, beyond the therapeutic time window of tPA. Methods alpha HMGB1 antibody, tPA and control IgG were dissolved in normal saline and administered intravenously into the tail vein of the mice after reperfusion. Infarct volume, hemorrhagic volume, brain swelling, functional outcomes and levels of pro-inflammatory cytokines, such as HMGB1. interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, were evaluated 24h after MCAO. Results tPA treatment was not only ineffective but also caused a massive intracerebral hemorrhage. Treatment with alpha HMGB1 antibody reduced the infarct volume and swelling and ameliorated neurologic impairment and motor coordination without hemorrhagic complications by inhibiting HMGB1 activity. Moreover, the alpha HMGB1 antibody suppressed pathways of secondary inflammatory responses, such as IL-6 and TNF-alpha, after cerebral ischemia. Conclusion These results indicate that alpha HMGB1 antibody may be therapeutically efficient in the delayed phase of ischemia, where tPA treatment is no longer an eligible option. Treatment with an alpha HMGB1 antibody may be an effective therapeutic option in patients who exceed the tPA therapeutic time window. Copyright (C) 2022 Wolters Kluwer Health. Inc. All rights reserved.