Background
Intracerebral hemorrhage (ICH) is recognized as a serious clinical problem lacking effective treatment. High mobility group box-1 (HMGB1) exhibits inflammatory cytokine-like activity once released into the extracellular space from the nuclei. We previously demonstrated that intravenous injection of rat anti-HMGB1 monoclonal antibody (mAb) remarkably ameliorated brain injury induced by hemorrhage in the striatum of rat. In the present study, we will examine whether and how humanized anti-HMGB1 mAb effects on ICH injury in common marmoset, one of the non-human primates, which will provide insights into a new treatment for human ICH diseases.
Method
Collagenase IV was delivered into the right striatum to make ICH model. Humanized anti-HMGB1 mAb or control IgG was administrated through the tail vein after ICH induction. During the experiment, body weight, routine blood test, plasma HMGB1 level and plasma 4- HNE level was examined at different time points of ICH (pre, 1d, 2 d, 4 d, 7 d and 12 d after ICH). Plasma inflammatory cytokines were detected by cytometric bead array assay. Grip strength test was performed to evaluate neurological function at different time points. Finally, brains were fixed and embedded in paraffin for immunohistochemistry.
Result
We show that administration of humanized anti-HMGB1 mAb inhibited the release of HMGB1 into the extracellular space in the peri- hematoma area. Plasma HMGB1 were reduced in association with decreased expression of plasma inflammatory cytokines by anti- HMGB1 mAb. As one of the oxidative stress biomarkers, 4-HNE adduct was accumulated mostly in microglia and neurons at the border of hematoma area, while located specifically in migrated microglia surrounding the pericytes in peri-hematoma area. Administration of anti-HMGB1 mAb decreased the 4-HNE accumulation in the brain and plasma. Moreover, anti-HMGB1 mAb reduced body weight loss and improved the behavioral performance.
Conclusion
We conclude that intravenous injection of humanized anti-HMGB1 mAb has potential as a novel therapeutic strategy ICH disease.